USE OF RASAGILINE FOR THE TREATMENT OF RESTLESS LEGS SYNDROME

Information

  • Patent Application
  • 20210386690
  • Publication Number
    20210386690
  • Date Filed
    August 11, 2021
    2 years ago
  • Date Published
    December 16, 2021
    2 years ago
Abstract
Disclosed are methods for the treatment of Restless Legs Syndrome comprising administering an amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof.
Description

Throughout this application various publications, published patent applications and published patents are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.


BACKGROUND OF THE INVENTION

Restless Legs Syndrome (“RLS”, also known as Ekbom Syndrome) is a neurological condition that expresses itself as an overwhelming urge to move the legs, usually caused by uncomfortable or unpleasant sensations in the legs at rest. Movement of the legs temporarily alleviates the discomfort. (Jones et al., Restless Legs Syndrome—A Review, Eur. J. Vasc. Endovasc. Surg., December 1997, 14(6):430-2)


The sensations occur during periods of inactivity, and are thus most intense in the evening and at night. RLS often causes difficulty staying or falling asleep, which leads to feelings of daytime tiredness or fatigue. RLS may cause involuntary jerking of the limbs during sleep and sometimes during wakefulness. Because of the nature of these symptoms, RLS is one of the most prevalent causes of sleep disorders such as sleep disturbance and insomnia. (Fox, G. N., Restless Legs Syndrome, American Family Physician, January 1986, 33(1):147-52)


RLS can occur at any age but increases in frequency as persons grow older. (Thorpy J. Michael. New Paradignms in the treatment of restless legs syndrome. Neurology 2005; 64: S28-S33) It afflicts about 8% of the general population. (see, rls.org/)


At least 80% of RLS patients experience periodic leg movements (PLMs), stereotyped, repetitive flexion movements of the legs that occur approximately every 5-90 seconds when the patient is asleep or lying down resting. (Hening A Wayne et al. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004, 27: 560-583.) Both the sensations in the limbs and the PLMs can profoundly disrupt sleep (getting to sleep and staying asleep). This can lead to excessive daytime sleepiness as well as depression and anxiety and may have a significant negative impact on quality of life.


Treatment of RLS can be difficult and often requires trying different drugs and dosage regimes. (The Merck Manual, 17th Ed. 1999, 1416) The primary pharmacologic treatment of RLS is principally with two classes of medications: dopaminergic agents and opiate agents. (Restless Legs Syndrome Foundation, Inc. Medical Bulletin, April 2004, pg. 15)


Nearly all patients with RLS show at least an initial positive therapeutic response to dopamine precursor levodopa (L-dopa) (either alone or with a dopa decarboxylase inhibitor like carbidopa) at dosages very low compared with those prescribed in the treatment of Parkinson's disease. (Montplaisir J. et al., Restless Legs Syndrome and Periodic Movements in Sleep: Physiopathology and Treatment with L-dopa, Clin. Neuropharmacol., 1986, 9(5):456-463) This initial response, however, is not universally maintained. The drawback of L-dopa therapy lies in the fact that in many patients its effectiveness tapers off and/or the RLS problem is shifted toward the morning hours (rebound) or the disorder is aggravated with the problem occurring event during the day (augmentation). (Guilleminault C. et al., Dopaminergic Treatment of Restless Legs and Rebound Phenomenon, Neurology, 1993, 43(2):445; and Allen R. P., Augmentation of the Restless Legs Syndrome with Carbidopa/Levodopa, Sleep, 1996, 19(3):205-213)


Dopamine-receptor agonists such as pergolide and pramipexole, known by the trade name Mirapex [available from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn.], provide well-established and effective treatment for RLS. However, they have been reported to cause major side effects. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514; and Silber M. H. et al., Pergolide in the Management of Restless Legs Syndrome: An Extended Study, Sleep, 1997, 20(10):878-882) In fact, all of the dopamine agonists can be used to treat RLS but with a negative aspect in that, usually in the beginning and as a function of the dosage administered, they lead to such side effects as nausea, vomiting, dizziness, hypotension, constipation or insomnia. (Medical Bulletin, infra at pg. 17)


Opiates are effective against RLS as well, although often at relatively high doses. (Walters, A. S. et al., Successful Treatment of the Idiopathic Restless Legs Syndrome in a Randomized Double-Blind Trial of Oxycodone Versus Placebo, Sleep, 1993, 16(4):327-332) However, because of the risk of addiction and progressive tolerance these substances are suitable for therapeutic application to a limited extent at best.


Benzodiazepines such as clonazepam and anticonvulsants such as gabapentin and carbamazepine have also been shown to alleviate the symptoms of RLS. (Medical Bulletin, infra at pg. 19) However, side effects similar to those associated with the treatments described above limit use. Addiction and daytime sedation are problematic with benzodiapenes, which does not prevent movement but only prevents awakening. (Id.) High dosages are required in anticonvulsant treatments. Furthermore, it is thought that anticonvulsants fail to resolve the full spectrum of elements of RLS. (Telstad W. et al., Treatment of the Restless Legs Syndrome with Carbamazepine; A Double Blind Study, Br. Med. J. (Clin. Res. Ed.), 1984, 288(6415):444-446)


Valproate has also shown benefit for RLS, but the side effect of weight gain has limited its acceptance. (Dinesin H. et al., Weight Gain During Treatment With Valproate, Acta. Neurol. Scan., 1984, 70(2):65-69)


Clonidine, originally developed as an antihypertensive agent and miotic, has also been examined for its effectiveness in the treatment of RLS. While it was found that soporiferous latency was reduced, it had no effect on the quality of sleep, the frequency of waking up or periodic leg movement during sleep. Given that more efficacious substances are available for monotherapy, clonidine is not currently recommended as an alternative form of therapy except in limited situations. (U.S. Patent Publication No. 2001/0053777, published Dec. 20, 2001)


Therefore, there exists a need for an effective, alternative treatment and related treatment regime options for individuals who are afflicted with RLS. More particularly, there exists a need for treatments that do not induce the unwanted effects observed in modern therapeutics of RLS.


SUMMARY OF THE INVENTION

This subject invention provides a method of treating a subject suffering from Restless Legs Syndrome which comprises administering to the subject an amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptably salt thereof, effective to treat the subject.


The subject invention also provides a method of alleviating a symptom of Restless Legs Syndrome in a subject afflicted with Restless Legs Syndrome comprising administering to the subject an amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof effective to alleviate the symptom of Restless Legs Syndrome in the subject.


The subject invention also provides a pharmaceutical composition comprising in unit dosage form R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and at least one of pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin.


The subject invention also provides a pharmaceutical composition for use in the treatment of, or alleviation of symptoms of, Restless Legs Syndrome, which comprises a therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.


The subject invention also provides use of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of, or alleviation of symptoms of, Restless Legs Syndrome.


The subject invention also provides a pharmaceutical composition comprising in unit dosage form R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and pramipexole.







DETAILED DESCRIPTION

The subject invention provides a method of treating a subject suffering from Restless Legs Syndrome which comprises administering to the subject an amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptably salt thereof, effective to treat the subject.


The subject invention also provides a method of alleviating a symptom of Restless Legs Syndrome in a subject afflicted with Restless Legs Syndrome comprising administering to the subject an amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof effective to alleviate the symptom of Restless Legs Syndrome in the subject.


In an embodiment, the symptom may be any of tingling in the legs, cramps in the legs, pain in the legs or restlessness in the legs.


In the methods, the IRLS Rating Scale score of the subject decreases compared to the baseline.


In an embodiment of the methods, the decrease is a 20% decrease, preferably a 30% decrease, more preferably a 40% decrease, yet more preferably a 50% decrease of the IRLS Rating Scale Score.


In an embodiment, the amount of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof may be from 0.01 mg to 20 mg per day. By 0.01 mg to 20 mg it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; 1, 2 . . . 19 mg unit amounts are included as embodiments of this invention.


In a further embodiment, the therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof may be from 0.5 mg to 5 mg per day.


In a specific embodiment, the amount may be 1.0 mg. By 0.5 mg to 5 mg it is meant that all tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.6, 0.7 . . . 0.9; 1, 2 . . . 4 mg unit amounts are included as embodiments of this invention.


In an embodiment, a dose of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof may be administered 1 to 4 times a day.


In a further embodiment, a dose of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof may be administered once a day.


Furthermore, an evening dose of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof may be administered to a subject 1 to 3 hours before the subject goes to bed.


Yet furthermore, a second dose is administered to the subject 3 to 7 hours before the evening dose.


In another embodiment, a dose of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof is administered to the subject at 3 to 7 hour intervals throughout the day.


In an embodiment, the administration is of R(+)-N-propargyl-1-aminoindan.


In a further embodiment, the administration is of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.


The pharmaceutically acceptable salt of the methods may be esylate, mesylate, sulfate or tartrate.


In a specific embodiment, the pharmaceutically acceptable salt may be mesylate.


In a further embodiment, the therapeutically effective amount of R(+)-N-propargyl-1-aminoindan mesylate may be 1.66 mg per day.


1 mg of the base compound R(+)-N-propargyl-1-aminoindan amounts to 1.66 mg of R(+)-N-propargyl-1-aminoindan mesylate.


In an embodiment, the administration may be oral, parenteral, rectal or transdermal administration.


In a further embodiment of the invention, the methods further comprise administration of carbidopa, levodopa, pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin.


In an embodiment, the administration of R(+)-N-propargyl-1-aminoindan or the salt substantially precedes the administration of any of carbidopa, levodopa, pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin.


In a further embodiment, the administration of R(+)-N-propargyl-1-aminoindan or the salt is contemporaneous with the administration of any of carbidopa, levodopa, pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin.


The R(+)-N-propargyl-1-aminoindan or the pharmaceutically acceptable salt thereof may be in a pharmaceutical composition when used in the methods.


In an embodiment, the pharmaceutical composition is in tablet form.


In an embodiment, the pharmaceutical composition is in a form suitable for transdermal administration.


In an embodiment, the pharmaceutical composition is in a form suitable for sublingual administration.


The subject invention also provides a pharmaceutical composition comprising in unit dosage form R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and at least one of pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin.


The subject invention also provides a pharmaceutical composition comprising in unit dosage form R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and pramipexole.


In an embodiment, the amount of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable salt thereof is from 0.5 mg to 5 mg.


In a further embodiment, the amount of R(+)-N-propargyl-1-aminoindan is 1 mg.


In a further embodiment, the R(+)-N-propargyl-1-aminoindan is the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.


In a further embodiment, the pharmaceutically acceptable salt is esylate, mesylate, sulfate or tartrate.


In a further embodiment, the pharmaceutically acceptable salt is mesylate.


In a further embodiment, the amount of R(+)-N-propargyl-1-aminoindan mesylate is 1.66 mg.


In a further embodiment, the amount of pramipexole is from 0.125 mg to 0.6 mg.


In a further embodiment, the amount of pramipexole is from 0.375 mg to 6.0 mg.


In a further embodiment, the amount of pramipexole is 0.6 mg.


In a further embodiment, the pramipexole is in a pharmaceutically acceptable salt form.


In a further embodiment, the pharmaceutically acceptable salt form is pramipexole dihydrochloride.


In a further embodiment, the amount of pramipexole dihydrochloride is 0.6 mg.


In a further embodiment, the amount of pramipexole dihydrochloride is 0.75 mg.


In a further embodiment, the amount of pramipexole is from 0.125 mg to 0.6 mg.


In a further embodiment, the amount of pramipexole is from 0.375 mg to 6.0 mg.


In a further embodiment, the amount of pramipexole is 0.6 mg.


In a further embodiment, the pramipexole is in a pharmaceutically acceptable salt form.


In a further embodiment, the pharmaceutically acceptable salt form is pramipexole dihydrochloride.


In a further embodiment, the amount of pramipexole dihydrochloride is 0.6 mg.


In a further embodiment, the amount of pramipexole dihydrochloride is 0.75 mg.


The subject invention also provides a pharmaceutical composition for use in the treatment of, or alleviation of symptoms of, Restless Legs Syndrome, which comprises a therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.


The subject invention also provides use of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of, or alleviation of symptoms of, Restless Legs Syndrome. Such use can have the same embodiments as those specifically disclosed herein in the context of a method.


The present invention thus provides the R-(+)-enantiomer of N-propargyl-1-aminoindan [“R(+)PAI”] of the formula (I):




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and pharmaceutically acceptable acid additions salts thereof for the treatment of human patients for Restless Legs Syndrome (“RLS”). The present invention also provides pharmaceutical compositions comprising the compound R(+)PAI, their preparations and methods of treatment of RLS with the pharmaceutical compositions.


The subject invention also provides a method for the treatment of RLS with rasagiline, wherein, the patient has previously been diagnosed and treated for RLS and developed symptoms of augmentation, i.e. a common consequence of long term treatment in which the symptoms of RLS become more severe, occur earlier in the evening, and spread to other parts of the body.


Rasagiline is the INN (International Nonproprietary Name) and USAN (United States Adopted Name) of the chemical substance R-(+)-N-propargyl-1-aminoindan.


R(+)PAI may be obtained by optical resolution of racemic mixtures of R and S-enantiomer of N-propargyl-1-aminoindan (PAI). Such a resolution can be accomplished by any conventional resolution method, well known to a person skilled in the art, such as those described in “Enantiomers, Racemates and Resolutions” by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, N.Y., 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. Another example of a suitable resolution method is the formation of diastereomeric salts with a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by recrystallisation to isolate the diastereomeric salt of the desired R enantiomer.


The racemic mixture of R and S enantiomers of PAI may be prepared, e.g. as described in WO95/11016. The racemic mixture of PAI can also be prepared by reacting 1-chloroindan or 1-bromoindan with propargylamine. Alternatively, this racemate may be prepared by reacting propargylamine with 1-indanone to form the corresponding imine, followed by reduction of the carbon-nitrogen double bond of the imine with a suitable agent, such as sodium borohydride.


In accordance with this invention, R(+)PAI can also be prepared directly from the optically active R-enantiomer of 1-aminoindan by reaction with propargyl bromide or propargyl chloride in the presence of an organic or inorganic base and optionally in the presence of a suitable solvent. A preferred method of preparation of the aforementioned compound is the reaction between R-1-aminoindan with propargyl chloride using potassium bicarbonate as a base and acetonitrile as solvent.


The compound R(+)PAI may be prepared as pharmaceutical compositions particularly useful for the treatment of RLS. Such compositions may comprise the compound of R(+)PAI or pharmaceutically acceptable acid addition salts thereof, together with pharmaceutically acceptable carriers and/or excipients. In the practice of this invention, pharmaceutically acceptable salts include, but are not limited to, the mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p-tolunesulfonate, benzoate, acetate, phosphate and sulfate salts.


The compound pramipexole is a non-ergoline dopamine agonist effective as an adjunct therapy to levodopa in the treatment of patients with advanced Parkinson's disease experiencing motor effects. It is also effective as a monotherapy in early Parkinson's disease patients where it has shown improvement in daily living and motor symptoms. Pramipexole has been determined to act at dopamine D2 receptors, specifically at presynaptic dopamine D2 autoreceptors and postsynaptic dopamine D2 receptors. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.


Pramipexole may be administered from 0.375 to 6.0 mg/day and in unit dosage from 0.125 to 1.5 mg. Pramipexole may be administered orally, inraperitoneally, subcutaneously or intravenously. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.


Pramipexole may be in the form of pramipexole base. In the practice of this invention, a pharmaceutically acceptable salt form of pramipexole includes pramipexole dihydrochloride. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.


Pramipexole may be initially administered at a dosage which is gradually increased until symptoms are relieved. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.


Pramipexole may be administered 3 times daily. (Dooley M. et al., Pramipexole: A Review of Its Use in the Management of Early and Advanced Parkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.


The compositions may be prepared as medicaments to be administered orally, parenterally, rectally or transdermally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions; for parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion; for rectal administration there are provided suppositories with hydrophilic or hydrophobic vehicles; and for topical application as ointments and transdermal delivery there are provided suitable delivery systems as known in the art.


Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Pat. No. 6,126,968 to Peskin et al., issued Oct. 3, 2000. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).


Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.


Rasagiline mesylate in a 1 mg tablet is commercially available for use in Parkinson's disease treatment as Azilect® from Teva Pharmaceutical Industries, Ltd. (Petach Tikva, Israel) and H. Lundbeck A/S (Copenhagen, Denmark). See, also AZILECT®, Physician's Desk Reference (2006), 60th Edition, Thomson Healthcare. The cognitive and behavioral adverse events of hallucinations, confusion, depression, somnolence and other sleep disorders in subjects treated with Azilect® are few and do not exceed the incidence seen in subjects receiving placebo by more than 3 percent. (Parkinson Study Group, Tyramine Challenge to Assess the Safety of Rasagiline Monotherapy in a Placebo-Controlled Multicenter Trial for Early Parkinson's Disease (The TEMPO Study), Neurology, 2001, 56:A345) The most commonly reported adverse events in rasagiline-treated subjects are pain, headache and dizziness. Side effects typically associated with other dopaminergic medications, such as hallucinations, somnolence, edema, nausea, vomiting, and diarrhea, are infrequently reported in rasagiline-treated subjects. (Stern et al., Double-Blind, Randomized, Controlled Trial of Rasagiline as Monotherapy in Early Parkinson's Disease Patients, Mov. Disord., 2004, 19(8):916-923)


R(+)PAI compositions may be used alone to treat RLS, or alternatively, they may be used as an adjunct to existing RLS treatments. R(+)PAI may be administered at different times and separate from other RLS treatments, or as a combined pharmaceutical composition of R(+)PAI with at least one of carbidopa, levodopa, pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin. Thus, for example, a pharmaceutical composition for oral use in the form of tablets or capsules may comprise R(+)-N-propargyl-1-aminoindan, Levodopa, and a decarboxylase inhibitor. Such a composition may comprise 0.01-20 mg of R(+)-N-propargyl-1-aminoindan, 50-100 mg of Levodopa, and 12.5-50 mg of benserazide.


The preferred dosages of R(+)PAI in any of the disclosed compositions may be within the following ranges: for oral or suppository formulations 0.01-20 mg per dosage unit to be taken daily and more preferably 0.5-5 mg per dosage unit to be taken daily may be used; and for injectable formulations 0.05-10 mg/ml per dosage unit to be taken daily and more preferably 0.5-3 mg/ml per dosage unit to be taken daily may be used.


By 0.01-20 mg it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; and 1, 2 . . . 19 mg unit amounts are included as embodiments of this invention.


R(+)PAI is effective and suitable for use in the treatment of RLS, both alone and in combination with other RLS treatments.


Furthermore, unlike several known treatments of RLS, the use of rasagiline as the active ingredient for treating RLS improves the subject's condition without causing undesirable side effects. The subject is a human subject.


EXPERIMENTAL DETAILS
Example 1















R(+)-N-propargyl-1-aminoindan mesylate
3.12 mg/tablet


Mannitol
62.5 mg/tablet


Maltodextrin (Maltrin 150)
36.0 mg/tablet


Croscarmellose sodium (Ac-Di-Sol)
 2.1 mg/tablet


Talc
 1.5 mg/tablet









Example 2















RW-N-propargyl-1-aminoindan mesylate
 1.56 mg/tablet


Mannitol
79.14 mg/tablet


Starch
 10.0 mg/tablet


Pregelatinized starch
 10.0 mg/tablet


Colloidal silicon dioxide
 0.6 mg/tablet


Talc
 2.0 mg/tablet


Stearic acid
 2.0 mg/tablet









Example 3















R(+)-N-propargyl-1-aminoindan mesylate
 3.12 mg/tablet


Mannitol
76.58 mg/tablet


Starch
 10.0 mg/tablet


Pregelatinized starch
 10.0 mg/tablet


Colloidal silicon dioxide
 0.6 mg/tablet


Citric acid
 1.0 mg/tablet


Talc
 2.0 mg/tablet









Example 4















R(+)-N-propargyl-1-aminoindan mesylate
 3.12 mg/tablet


Mannitol
69.88 mg/tablet


Lactose (hydrous)
 14.0 mg/tablet


Starch
 14.0 mg/tablet


Glyceryl Behenate (Compitrol 888 ATO)
 2.0 mg/tablet









Example 5















R(+)-N-propargyl-1-aminoindan mesylate
 3.12 mg/tablet


Mannitol
77.28 mg/tablet


Starch
 10.0 mg/tablet


Starch STA-RX 1500
 10.0 mg/tablet


Colloidal silicon dioxide, Aerosil
 0.6 mg/tablet


Hydrogenated vegetable type I
 2.0 mg/tablet


(Sterotex Dritex)









Example 6—Rat Model of RLS

6-hydroxydopamine is an agent that selectively disrupts or destroys catecholaminergic systems. Thus, stereotaxic bilateral 6-hydroxydopamine lesions into the nucleus of dopaminergic diencephalic spinal neurons (A11) are performed to effect behavior consistent, although not specific, with what would be expected in a rat model of RLS. (Ondo W. G. et al., Clinical Correlates of 6-Hydroxydopamine Injections into A11 Dopaminergic Neurons in Rats: A Possible Model for Restless Leg Syndrome, Mov. Disord., 2000, 15(1):154-8)


Multiple blindly-rated video epochs demonstrate an increased average number of standing episodes and increased total standing time but similar total sleep time in lesioned rats when compared with control rats. However, treatment of the lesioned rats with R(+)PAI mesylate results in fewer standing episodes and less total standing time when compared with untreated lesioned rats.


Example 7—RLS Model Spontaneously Occurring During Sleep of Rats

Periodic limb movements in sleep (PLMS) are often associated with RLS. In a group of old rats 16-20 months, sleep-wake behavior is recorded and hindlimb movements are detected by means of a magneto-inductive device during two 12-h light periods (Baier P. C. et al., Assessment of spontaneously occurring periodic limb movements in sleep in the rat, J. Neurol. Sci. 2002; 198(1-2): 71-77). Periodic hindlimb movements (PHLM) during nonrapid eye movement sleep (NREM) are identified according to modified human criteria in some of the rats, which are then selected for the rasagiline study. Half the rats are treated daily with rasagiline while the other half receive vehicle. Incidence of PHLM is determined for 3 consecutive nights, beginning 7 days after onset of treatment. It is demonstrated that rasagiline-treated rats have significantly fewer PHLM than vehicle-treated rats.


Example 8

The 1 mg tablet of R(+)PAI mesylate is investigated in placebo-controlled, double-blind, randomized clinical tests covering in a study adult patients who are suffering from moderate to severe primary Restless Legs Syndrome.


Randomization in terms of gender, age and severity of prior illnesses is reasonably balanced. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) are excluded.


After gradual and complete termination of any preceding L-dopa treatment and a break in the therapy (washout) the patients are treated with R(+)PAI.


Over a treatment period of days the patients of one group are treated with a 0.5 mg dosage and the patients of another group are treated with 1 mg. For a comparison the patients in the placebo group are treated with a placebo.


Severity of symptoms is measured with a rating scale developed by the International Restless Legs Syndrome Study Group (“IRLSSG”) (http://www.irlssg.org/). Use of the scale is common for clinical assessment, research and therapeutic trials with RLS. The overall IRLSSG rating is derived from the individual values discussed below.


First, an initial starting value is determined for each patient participating in the study. This is done by adding up the individual IRLSSG parameter values as of Day 0, i.e. before treatment. Over the course of treatment the IRLSSG values are compared with the starting value and any changes from that starting value are recorded. Finally, the average improvement of the IRLSSG value over the starting value is determined by calculating the average of all test subjects. The resulting value is called CAS—(complete analysis set) randomized average change from the starting value of the overall IRLSSG rating. The term “randomized” indicates that in terms of their different prespecified dosages the patients are subjected to prior double-blind randomization.


Results


Between the starting value and that established after treatment, a significant improvement of the IRLSSG values is recorded in comparison with the placebo group.


At the end of the treatment both patient groups report that subjective symptoms such as tingling, cramps and pain in the legs, restlessness in the legs during the night, and difficulties falling or remaining asleep either disappear or diminish to a tolerable minimum.


The patients also report that the treatment does not or only to a very minimal extent causes any hallucinations, somnolence, edema, nausea, vomiting or diarrhea.


Accordingly, R(+)PAI is well tolerated and safe and leads to a distinct clinical improvement in patients in a moderate to severe stage of RLS.


An improvement of the IRLSSG value of 2 points compared to a placebo can be considered a success. An improvement by over 3 or 6 and more rating units constitutes an all the more significant therapeutic advance and is therefore the preferred objective of this invention.


Example 9

This was the first clinical study in which rasagiline was administered to RLS subjects. The dosage regimen of 1 mg/day rasagiline was chosen based on the optimal dosage regimen for the symptomatic treatment of PD. However, smaller doses than those required for the treatment of PD are expected to be efficacious in the treatment of RLS. Therefore, in the event that a subject could not tolerate the 1 mg daily dose of rasagiline, a daily dose of 0.5 mg rasagiline was permitted. Rasagiline was administered orally as a tablet. Both the 1 mg and 0.5 mg rasagiline tablets were beveled round tablets, flat, white to off-white, scored on one side, plain on the other side. Teva Pharmaceutical Industries Ltd. was responsible for the manufacture and primary packaging of study medications according to current Good Manufacturing Practice (cGMP) principles and guidelines applicable to investigational medicinal products.

























Week









12/




Week-
Week



Early




2a
0
Week
Week
Week
Termi-
Unsched-


Visit
(screen-
(base-
2
4
8
nation
uled


Week No.
ing)
line)
±4
±4
±4
±4
Visitb







Informed
X








consent









Inclusion/
X
X







Exclusion









criteria









Medical
X








history









Concomitant
X
X
X
X
X
X
X


medications









IRLS
X
X
X
X
X
X



Sleep Scale

X

X
X
X



CGI-I


X
X
X
X



RLS Quality

X

X
X
X



of Life









Questionnaire









Adverse events

X
X
X
X
X
X


AE follow lip





X



Laboratory test
X




X
X


including









β-hCGc









Vital signsd
X
X
X
X
X
X
X


ECG
X




X
X


Dermatological
X




X
X


evaluation









Study





X



termination









Retrieve


X
X
X
X
X


study drug









and assess









compliance









Dispense

X
X
X
X

X


study drug






a) The maximal interval between the screening and baseline visits should be 14 days. If, however, results from screening procedures are still pending after 14 days from the screening visit and the investigator has to wait until all results are available before determining a subject's eligibility, the interval between the screening and baseline visits may extend up to 21 days.




b) Procedures during an unscheduled visit are optional, except vital signs.




c) Pregnancy test relevant to women of childbearing potential only




d) Including weight and height at screening and weight at Visit Week 8/Early Termination







IRLS (International Restless Legs Scale)


The IRLS scale is comprised of 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. All items receive a grade in the range 0 to 4 (0=absence of a problem, 4=very severe problem) giving a maximum score of 40.


The investigator scored subjects on the IRLS at all scheduled study visits. The primary efficacy endpoint was based on the change from baseline to weeks 2, 4, and 8 in IRLS scores.


IRLS Scale


Each of 10 items were graded on a scale between 0 and 4 where 0 denotes the absence of a problem, and 4 a very severe problem. Table 1 shows the results; a low score indicates the absence of a problem and a high score indicates a very severe problem.









TABLE 1







Descriptive Statistics of IRLS Rating Scale and Change from Baseline Over Time











IRLS Total
IRLS Total (Absolute Change)
IRLS Total (Percent Change)






























Me-





Me-





Me-



Week
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max





BASE-
2
32.00
8.49
26.00
32.00
38.00
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
29.00
12.73
20.00
29.00
38.00
2
−3.00
4.24
−6.00
−3.00
0.00
2
−11.54
16.32
−23.08
−11.54
0.00


WEEK




















1




















VISIT
2
25.50
17.68
13.00
25.50
38.00
2
−6.50
9.19
−13.00
−6.50
0.00
2
−25.00
35.36
−50.00
−25.10
0.00


WEEK




















4




















VISIT
1
12.00

12.00
12.00
12.00
1
−14.00

−14.00
−14.00
−14.00
1
−53.85

−53.85
−53.85
−53.85


WEEK




















3









Clinical Global Impression-Global Improvement (CGI-I)


The CGI-I scale is a single item scale on which the investigator rated a subject's symptoms as very much improved, much improved, minimally improved, not changed, minimally worse, much worse, or very much worse. Subjects were scored on this scale at weeks 2, 4, and 8. The mean score at each of these time points was calculated as a secondary efficacy endpoint. Table 2 shows the results of the CGI-I Rating Scale. Subjects are scored on a scale of 1-7, where 1 indicates the subject's symptoms are very much improved and 7 indicates the subject's symptoms are very much worse.









TABLE 2







Descriptive Statistics of CGI-I Rating Scale









CGI-I Total













Week
N
Mean
SD
Min
Median
Max
















VISIT WEEK 2
2
3.50
0.71
3.00
3.0
4.00


VISIT WEEK 4
2
3.50
2.12
2.00
3.50
5.00


VISIT WEEK 8
1
1.00

1.00
4.00
1.00









RLS QoL Questionnaire


The Restless Leg Syndrome Quality of Life questionnaire (RLS QoL) assesses the impact of RLS on daily life, emotional well-being, social life and work life. It is an 18-item questionnaire with a total score ranging 0 to 100. Table 3 shows the results of this questionnaire. The lower the score, the greater the impact of RLS on quality of life.









TABLE 3







Descriptive Statistics of IRLS QoL Rating Scale and Change from Baseline Over Time











IRLS QoL Total
IRLS QoL Total (Absolute Change)
IRLS QoL Total (Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max





BASE-
2
46.25
30.05
25.00
46.25
67.50
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
62.92
41.84
33.33
62.92
92.50
2
16.67
11.79
8.33
16.67
25.00
2
35.19
2.62
33.33
35.19
37.04


WEEK 4




















VISIT
1
92.50

92.50
92.50
92.50
1
25.00

25.00
25.00
25.00
1
37.04

37.04
37.04
37.04


WEEK 8









(Abetz L. et al. Validation of the restless legs syndrome quality of life questionnaire. Value in Health, 2005; 8(2): 157-167)


The RLS QoL questionnaire was completed by the investigator at the baseline and Week 4, and 8 visits. The change from baseline to each post-baseline study visit was calculated as an additional efficacy endpoint.


Sleep Scale:


The Sleep Scale is a 12-item scale that provides a comprehensive view across almost all dimensions of sleep including daytime somnolence, sleep disturbance, sleep adequacy and sleep quantity. The investigator scored subjects on this scale at the baseline and Week 4, and 8 visits. The change from baseline to each post-baseline study visit was calculated as a secondary efficacy endpoint. (Hays, R. D. & Steward, A. L. (1992). Sleep measures. In A. L. Stewart & J. E. Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study approach (pp. 235-259), Durham, N.C.: Duke University Press.


Tables 4-12 show the results of the Sleep Rating Scale and change from baseline over time for each of the 9 dimensions scored by the Sleep Rating Scale. N is the number of participants in the study. A low score indicates the absence of problems and a high score indicates a very severe problem.









TABLE 4







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time











Sleep Disturbance Scale
Sleep Disturbance (Absolute Change)
Sleep Disturbance (Percent Change)






























Me-





Me-





Me-



Week
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max





BASE-
2
41.25
5.30
37.50
41.25
45.00
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
33.75
15.91
22.50
33.75
45.00
2
−7.50
10.61
−15.00
−7.50
0.00
2
−20.00
28.28
−40.00
−20.00
0.00


WEEK




















4




















VISIT
1
21.25

21.25
21.25
21.25
1
−16.25

−16.25
−16.25
−16.25
1
−43.33

−43.33
−43.33
−43.33


WEEK




















8
















TABLE 5







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time











Snoring Scale
Sleep Snoring (Absolute Change)
Sleep Snoring (Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max




























BASE-
2
40.00
56.57
0.00
40.00
80.00
2
0.00
0.00
0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


LINE




















VISIT
2
40.00
56.57
0.00
40.00
80.00
2
0.00
0.00
0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


WEEK 4




















VISIT
1
100.00

100.00
100.00
100.00
1
20.00

20.00
20.00
20.00
1
25.00

25.00
25.00
25.00


WEEK 8
















TABLE 6







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time












Sleep Short of Breath
Sleep Short of Breath



Short of Breath Scale
(Absolute Change)
(Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max





BASE-
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00
0







LINE




















VISIT
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00
0







WEEK 4




















VISIT
1
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00
0







WEEK 8
















TABLE 7







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time











Sleep Adequacy
Sleep Adequacy (Absolute Change)
Sleep Adequacy (Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Mitt
Median
Max
N
Mean
SD
Min
Median
Max





BASE-
2
40.00
28.28
20.00
40.00
60.00
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
55.00
49.50
20.00
55.00
90.00
2
15.00
21.21
0.00
15.00
30.00
2
25.00
35.36
0.00
25.00
50.00


WEEK 4




















VISIT
1
100.00

100.00
100.00
100.00
1
40.00

40.00
40.00
40.00
1
66.67

66.67
66.67
66.67


WEEK 8
















TABLE 8







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time












Sleep Somnolence




Somnolence Scale
(Absolute Change)
Sleep Somnolence (Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max




























BASE-
2
40.00
37.71
13.33
40.00
66.67
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
40.00
47.14
6.67
40.00
73.33
2
−0.00
9.43
−6.67
−0.00
6.67
2
−20.00
42.43
−50.00
−20.00
10.00


WEEK 4




















VISIT
1
13.33

13.33
13.33
13.33
1
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


WEEK 8
















TABLE 9







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time












Sleep Problems Index
Sleep Problems Index



Sleep Problems Index I
I (Absolute Change)
I (Percent Change)






























Me-





Me-





Me-



Week
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max





BASE-
2
33.33
23.57
16.67
33.33
50.00
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
26.67
33.00
3.33
26.67
50.00
2
−6.67
9.43
−13.33
−6.67
0.00
2
−40.00
56.57
−80.00
−40.00
0.00


WEEK




















4




















VISIT
1
0.00

0.00
0.00
0.00
1
−16.67

−16.67
−16.67
−16.67
1
−100.00

−100.0
−100.00
−100.00


WEEK




















8
















TABLE 10







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time












Sleep Problems Index
Sleep Problems Index



Sleep Problems Index II
II (Absolute Change)
II (Percent Change)






























Me-





Me-





Me-



Week
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max
N
Mean
SD
Min
dian
Max





BASE-
2
40.56
18.07
27.78
40.56
53.33
2
0.00
0.00
0.00
0.00
0.00
2
0.00
0.00
0.00
0.00
0.00


LINE




















VISIT
2
33.89
27.50
14.44
33.89
53.33
2
−6.67
9.43
−13.33
−6.67
0.00
2
24.00
33.94
−48.00
−24.00
0.00


WEEK




















4




















VISIT
1
11.67

11.67
11.67
11.67
1
−16.11

−16.11
−16.11
−16.11
1
−58.00

−58.00
−58.00
−58.00


WEEK




















8
















TABLE 11







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time












Sleep Quantity




Sleep Quantity (raw score)
(Absolute Change)
Sleep Quantity (Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max





BASE-
1
7.00

7.00
7.00
7.00
1
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


LINE




















VISIT
1
7.00

7.00
7.00
7.00
1
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


WEEK 4




















VISIT
1
7.00

7.00
7.00
7.00
I
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


WEEK 8
















TABLE 12







Descriptive Statistics of Sleep Rating Scale and Change from Baseline Over Time











Optimal Sleep Scale
Optimal Sleep (Absolute Change)
Optimal Sleep (Percent Change)

























Week
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max
N
Mean
SD
Min
Median
Max





BASE-
1
1.00

1.00
1.00
1.00
1
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


LINE




















VISIT
1
1.00

1.00
1.00
1.00
1
0.00

0.00
0.00
0.00
1
0.00

0.00
0.00
0.00


WEEK 4




















VISIT
1
1.00

1.00
1.00
1.00
1
0.00

0.00
0.00
0.00
I
0.00

0.00
0.00
0.00


WEEK 8









CONCLUSION

To date, 2 subjects have been enrolled in this open label pilot study of rasagiline's efficacy in Restless Legs Syndrome. These subjects had a mean baseline IRLS Rating Scale score of 32. After 2 weeks the mean score had decrease to 29. At 4 weeks, one subject had a score of 13 (indicating a 50% decrease from baseline). Another subject discontinued participation in the study, at week 4, with a score of 38, unchanged from this subject's baseline score. By 8 weeks, the remaining subject's IRLS score had decreased to 12 (a 54% decrease from baseline). Additionally, by eight weeks this subject had indicated that the RLS symptoms were “Very Much Improved” on the CGI-I rating scale. Also, by eight weeks this subject had an improvement of 37% in the IRLS Quality of Life Questionnaire compared to baseline. In addition, by eight weeks, this subject had an improvement of 58% in the Sleep Problems Index II statistic measured as part of the Sleep Scale. In summary, in at least a subset of RLS patients, rasagiline has been shown to have a clinically significant effect on the symptoms of RLS.

Claims
  • 1. A pharmaceutical composition comprising in unit dosage form R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and at least one of pergolide, pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropinirole or clonidin.
Parent Case Info

This application is a continuation of U.S. Ser. No. 14/524,993, filed Oct. 27, 2014, which is a continuation of U.S. Ser. No. 11/731,493, filed Mar. 30, 2007, which claims benefit of U.S. Provisional Application No. 60/788,617 filed Apr. 3, 2006, the entire contents of each of which in their entireties are hereby incorporated by reference.

Provisional Applications (1)
Number Date Country
60788617 Apr 2006 US
Continuations (15)
Number Date Country
Parent 17306106 May 2021 US
Child 17399753 US
Parent 17152514 Jan 2021 US
Child 17306106 US
Parent 17065811 Oct 2020 US
Child 17152514 US
Parent 16913633 Jun 2020 US
Child 17065811 US
Parent 16815979 Mar 2020 US
Child 16913633 US
Parent 16696568 Nov 2019 US
Child 16815979 US
Parent 16543164 Aug 2019 US
Child 16696568 US
Parent 16405468 May 2019 US
Child 16543164 US
Parent 16233046 Dec 2018 US
Child 16405468 US
Parent 16102148 Aug 2018 US
Child 16233046 US
Parent 15895962 Feb 2018 US
Child 16102148 US
Parent 15697935 Sep 2017 US
Child 15895962 US
Parent 15096038 Apr 2016 US
Child 15697935 US
Parent 14524993 Oct 2014 US
Child 15096038 US
Parent 11731493 Mar 2007 US
Child 14524993 US