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CA2133514A1 - Restorative neuropharmacological agent for motor and speech disturbance - Google Patents

Restorative neuropharmacological agent for motor and speech disturbance

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Publication number
CA2133514A1
CA2133514A1 CA002133514A CA2133514A CA2133514A1 CA 2133514 A1 CA2133514 A1 CA 2133514A1 CA 002133514 A CA002133514 A CA 002133514A CA 2133514 A CA2133514 A CA 2133514A CA 2133514 A1 CA2133514 A1 CA 2133514A1
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Canada
Prior art keywords
pharmaceutically
dops
threo
salt
effective amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002133514A
Other languages
French (fr)
Inventor
Katsuhiro Nishino
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Sumitomo Pharmaceuticals Co Ltd
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Sumitomo Pharmaceuticals Co Ltd
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Filing date
Publication date
Application filed by Sumitomo Pharmaceuticals Co Ltd filed Critical Sumitomo Pharmaceuticals Co Ltd
Publication of CA2133514A1 publication Critical patent/CA2133514A1/en
Abandoned legal-status Critical Current

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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

Abstract

A restorative neuropharmacological method of treating motor or speech disturbance comprising administration of L- or DL-threo-DOPS or its pharmaceutically acceptable acid-addition-salt to a patient. Restoration from motor and speech disturbance from central nervous system disturbance is providedby stimulating the central nervous system so as to enhance intrinsic neuroplasticity and thus increasing the functional compensation, while conventional physical therapy alone cannot provide such recovery, because less attention has been paid to the pathophysiology in the central nervous system after stroke or head injury.

Description

f ~ 2133~

Thi~ invention relates to a restorative neuropharmacological agent for motor and speech disturbance originating iro~ central nerYous system disorders.

L-threo-DOPS (Droxidopa) is a central norepinephrine prec~lsor and is known as an active ingredient for norepinePhrine activated nerve function imProving agents. Clinically. L-threo-DOPS is used to improve impotent ~eet and orthostatic dizziness in Parkinson's disease (stage 3 in the degree of severity according to Yahr) and also to impro~e orthostatic hYPotensionl SYncope and orthcstatic di~ziness in familial an~loid Polyne~ropathy or Shy-Drager SYndrome.Conventionally. impr~vement of ~ntor and speech distur~ance uriginating fram central ner~ous system disorders was deemed di~ficultly to treat ~nd the development of such a therapeutic agent was generally be~ieved to be imPossible in the medicine.

The object of this inventivn is to dispel this genera~ belief in the medicine and pro~ide restoration from motor and speech disturbance originating Irom central nervous syste~ disorders by stimulating the central nervous system and thus increasing the functional compensation based on the intrinsic plasticity of the central nervous sYste~ while conYentional PhYsical therapy alone cannot provide such recovery.

213351~

By a broad aspect of the present invention the use is provided of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance, or for treating speech disturbance, or for treating motor or speech disturbance due to stroke or head trauma, or for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
By another aspect of this invention, the use is provided of a peripheral decarboxylase inhibitor and a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance, or for treating motor disturbance, or for treating speech disturbance, or for treating motor or speech disturbance due to stroke or head trauma, or for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
By yet another broad aspect of this invention, the use is provided of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance, or for treating motor disturbance, or for treating speech disturbance, or for treating motor or speech disturbance due to stroke or head trauma, or for treating motor or 2133Sl~

speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
By yet another broad aspect of this invention, the use is provided of a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance, or for treating motor disturbance, or for treating speech disturbance, or for treating motor or speech disturbance due to stroke or head trauma, or for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
By still another broad aspect of this invention, the use is provided of a mixture of a peripheral decarboxylase inhibitor and a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance, or for treating motor disturbance, or for treating speech disturbance, or for treating motor or speech disturbance due to stroke or head trauma, or for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
By a still further broad aspect of this invention, the use is provided of a preparation containing a peripheral lB

21~351~

decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L-threo-DOPS
or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance, or for treating motor disturbance, or for treating speech disturbance, or for treating motor or speech disturbance due to stroke or head trauma, or for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
In each of the above uses, by a variant of such aspects, the peripheral decarboxylase inhibitor is benserazide or carbidopa.
By another aspect of this invention, a pharmaceutical composition is provided comprising a peripheral decarboxy-lase inhibitor, a pharmaceutically-effective amount of L-or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof, and a pharmaceutically-acceptable carrier.
By yet another aspect of this invention, a pharma-ceutical composition is provided comprising a peripheral decarboxylase inhibitor, a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof, and a pharmaceutically-acceptable carrier.
By variants of the two above aspects of the invention, in such pharmaceutical compositions, the peripheral decarboxylase inhibitor is benserazide or carbidopa.

2I33~14 In order to achieve the object set forth above. the restorative neurological therapeutic ~gent for mator and speech disturbance according to this invention characteristically contains l-threo-DOPS as a~ active ingredient.
~ L-threo-DOPS (Droxidopa) is ~-)-(2R. 3R)-2-amino-3-hydroxy-3-(3. 4- -dihydroxyphenyl) propiollic acid (according to the JAN no~enclature) ~r (-)-threo-3-(~ ~-dihydroxyphenyl) L-serine (acoDrding to the INN nomenclature).
the structural formula of which is shown below.

OH H
HO~C C COOH

H o H NH2 L-threo-DOPS. v~hose ~olecular for~ula is Cg Hl~NO~ is ~hite or light brown crystals ~r crystalline powder with no taste or odor. DroxidoPa dissolves onlY
slightly in water, and dissolves Yery little in ether. ethanol and glacial acetic acid It is diffiçult to measure a clear melting point or decomposition point for L-threo-DOPS. L-threo-DOPS shows some change~s when the temperature is raised to the vicinity of 220 C. starts melting at 225 'C. and turns into a black liquid at around 230 CC. The PKa o~ L-threo-DOPS is 7.88. measured by the titration metho~ DL-threo- W PS. which contains 50% L-threo-DOPS. can also be used in this invention. Hereafter. L-threo-DOPS and DL-threo-DOPS are generically denoted as ~threo-DOPS~.
In this invention. threo-DOPS can be used in a pharmaceutically accePtable acid-addition-salt for~ as well. For example, inorganic acids e g., 213351~

hydrochloric acid, hydrobromic acid and sulfuric acid and organic acids e.g fumaric acid, citric acid, tartaric acid and succinic acid can be used to for~
an acid-addition-salt.
Threo-DOPS can be manufactured by means of prior art methods e.g. those described in USP4562263 and ~SP4480109.
SoTe af the prior art phar~acological features of threo-W PS are follows:
(1) it is directly converted to l-norepinephrine by the action of the aromatic L-amino acid decarboxylase which is widely distributed in a living body, and thus has an e~iect of replenishing norepinephrine, (2) it passes through the blood-brain barrier into the brain, (3) it specifically recovers no~epinephrine activated nerve functions which have decreased in the central and peripheral nervous syst~ and (4) it shows various actions via the adrenaline receptors in various tissues. The restorative neuroPharmacological agent for motor and speech disturbance according to this invention is effective in improving motor paralysis and motor aphasia after stroke due to subarachnoid hemorrhage, brain infarction, brain hemorrhage, etc. or post-traumatic brain injury wherein physical therapy alone cannot provide improvement, and is particularly effectivein increasing the recovery rate in acute stroke cases and enl~nced lecovely in certain chronic stroke cases. Such actions of threo-DOPS have not been brought to light before, and tbere has been no functional improve~ent a8ent which sho~s such actions.
The functional improvement agent ~hich has threo-DOPS as an active ingredient can be in any form including capsules, tablets, confection, pills, parvule, suppository, solution and ampules. The functional improvement agent which has threo-DOPS as an active ingredient can contain fillers, expanders, binders, dissolution retardants, surfactants, adsorbents, lubricants, coloring agents, perfumes, p~esel~atives, etc. Such Preparations can be manufactured fol~o~ing 2133~1~

a typical common method. This uni~ue functional improvement agent can also contain other pharmaceutically active ingredients as well. A prior art norepinephrine activated nerve function imProVing agent ~hich has L-threo-DOPS
as an active ingredient is commercially available under the name "DOPS"
(manufactured and distributed in Japan bY Sumitomo Pharmaceuticals ComPany.
Limited ).
~ n particular, the restorative neuropharmacological agent for motor and speech disturbance according to this invention should preferably be used together with a peripheral decarboxylase inhibitor such as benserazide (hereafter referred to as "BSZn) or carbidoPa tD promote transfer of threo-DOPS
into the brai~ To use them together, separate preparatians of threo-DOPS and of a peripheral decarboxylase inhibitor can be administered either at the same time or at different times, or a mixture of them can be administered BSZ can be nanufactured using a prior art metho~
For the administration method of the restorative neurophanmacological agent for motor and sPeech disturbance according to this invention. depending on the form it takes, oral administration, rectal administration, nasal administration,intravenous administration, hYpodermic administration, intramuscular administration, etc, are possible, of which oral administration is preferable.
The amount o~ oral administration of the restorative neuropharmacological agent according to-this invention is 60-1,200 ~g droxidopa for com~on adults per day, preferably 100-900 mg, and more preferably 100-400 mg. When a Peripheral decarboxylase inhibitor is contained, the amount of the peripheral decarboxylase inhibitor contained is empirically 1-10% of the amount of droxidopa preferably 2.5-7.5~. and more PreferablY about 5~ For examPle 5%
is particularly preferable for BSZ. However, depending on the age, weight, symptoms. and past history etc. of the subiect to whom the medication is 21335I~

administered. the amount of administr~tion of droxidopa and th~ periPheral decarboxylase inhibitor can be c ~ nged as aPproPriate In clinical examples.
administration of droxidopa alone has sho~n sufficient efficacy.

` Preparatians accordin~ to this invention are described below by referring to cxamples.
~Example 1. Preparing capsules]
- 200 weight parts of droxidop~ 167 weight parts of an excipient and 3 weight parts of a lubricant are homogeneously mixed. and e~ptY
ca~sules are filled with this mixture in such a ~ay that each caPsule contains 200 mg o~ droxidopa A capsule prep~ration is thus obtaine~

~xa~ple 2: Preparing capsules]
100 weight parts o~ droxidop~. 168 weight Parts oI an excipient and 2 weight parts of a lubricant are homogen~uusly mixed.
and e~pty capsules are filled with this mixture in such a way that each capsulecontains 100 ng of droxidopa A capsule preparation is thus obtained.
The excipient for ExamPles 1 and 2 described above is chosen from among lactose, white sugar, glucose. D-~annitol. potato starch. corn starch. wheat starch. calcium carbonate, calciu~ sulfate, anhydrous caicium phosphate. sodium bicarbonate. crystalline cellulose. a mixture of these, etc. The lubricant is chosen from anong mzgnesium stearat~ calc~um stearat~ talc. etc, Clinical testing ~as conducted to evaluate the effects of the restorative neurophar~acological agent for motor and sPeech disturbance according to this inventio~
Clinical subjects for motor disturbance were 2 cases after cerebral aneurysm 213351~

operations (subarachnoid henorrhage). 9 cases D~ brain henorrhage and 10 cases of brain infarction with chronic apoplectic paralysis, i.e. a total of 21 cases (12 males and 9 females. age 43-83 with an a~erage 61.9 t/- 2.5 years). For these clinical subiects. the average time elapsed from the onset had occurred w~s 100 days. Table 1 sho~s the 21 clinical subject cases and 6 control cases.

2133~14 T A B L E 1 Lis~ of ~he short tenm ad~inistration testing cases Cases ad~inistered L-DK~S ContrDI cases ~not adninistered L- W PS) Case Age Sex DiaBnosis~ IrproveEent Case Age Sex Diagnosis~ l~pron~nent . in PMS N~ in ~lS
1 43 ~enale BH Im~roved 1 46 Male ~H No chsnge 2 51 Fessle Bl l~roved 2 62 Uale Bl No chE~Ige 3 50 Maie BH ir~oroved 3 71 Pe~ale BH Nb chanBe 4 57 Pe~ale Bl Irproved 4 70 kale Bl l~proved 59 Male BH lmproved 5 6B Pe~ale Bl No change 6 64 Pe~ale B] Nb change 6 76 Male Bl No chE~lBe 7 66 ~er2le SAH Improved 8 47 Male BH No change BH: Brain hemorrhage 9 51 kale SAH In~oroved Bl: Brain infarction 61 ~ale Bl No chanse SAH: Subarachnoid he~nrrhage 11 60 Male Bl InProved 12 ~2 Female BH Im4roved 13 57 kale BH No change 14 76 hklle Bl lrproved 64 Usle B[ ~mproved 16 64 Female BH Inproved 17 83 kale Bl bproved 18 71 Female BH Irproved 19 73 ~ale 81 No change 20 75 Male Bl No charlge 51 ~ Fe~ale ~1 IDIproved First. the clinical subiects received physical therapy without administration of droxidoPa (L-DOPS). and then they were evaluated with FMS (Fugl-MeYer score),10-meter walkinB and the ~arthel index. The clinical subiects then received administration of 300 mg droxidopa (L-~OPS) per day for 2 days in addition to the physical theraPy~ and were evaluated with F~S. 10-meter walking and with the Barthel index.
As a result, of the 21 cases to whom droxidopa was administered. 15 cases showed improved F~S. i.e. FMS increased by 2 ~ t/- Q 5. which was higher thanO .
1 t/- ~.2 for the control cases. The t-test showed that P was less than 0.005.indicating a significant difference. For this FMS. 10 o~ the 21 cases showed improvement in upper limb motor function, 6 of the 21 cases showed imPrOVement in lower limb motor f~nction, and 3 of the 21 cases showed improved balance.
On the other hand, of the 6 c~ntrol cases without droxidopa administratio~ O
case. 1 case and O case, resPectively~ showed such improve~ent.
All of the 12 cases with central-facial palsy showed i~ProVement. On the other hand, none of 6 control cases showed imProvement. 19 cases of the ~1 Gases showed imProve~ent in the 10-0eter walking. Of these, one case showed improvement in the Barthel index, i.e. improvement in ADL ~activities of dailyliving).
After 1-2 weeks. droxidoPa was administered again for 2 consecutive days to 5 of the 1~ cases who had showed improvement in F~S of the 21 cases who had received 2 days of administration, and further improvement was observed for 3 cases. This indicates that mlore improvement in motor functions can be expectedby administering droxidopa over a longer period of time. The administration of droxidopa to the clinical subjects was then halted. but the leYel of the i~provement effect on ~otor functions was maintained.
Based on the above results, lon~ tenm administration testing was conducte~

The clinical subjects ~ere 10 neurological stable cases who had an onset of stroke 2 ~onths to 2 years before the testing, and 200-500 mg/day of droxidopa was ad~inistered for 2 weeks to 2 months. As a result. 7 cases showed improvement in the Barthel index. i.e. imProvement in AD~ (activities of daily living) was obser~ed for 7 cases of the 10 cases. The results were in~epe~dP~t of the time elapsed since onset of the illness. Table 2 shows the list of the 1~ clinical subject cases.

T A B L E 2 Lisl of the lonB ~er~ adDinistralion lesting cases Case Age Sex Diagnosis Improveme~l Amount of L-DOPS administered N~ in ADL per day x duration 1 43 Female ~rain ste~ infarclion Inpr w ed 200 mg x 2W
2 51 Penale Subarachnoid hemcrrhageNb change 2Q0 m8 x 2W
3 50 ~ensle Brain hemorrhage Improved 300 mg x 3W
g 57 kaIe Su~arachnoid hemorrha8eNo chan8e 200 mg x 4W
- t ~rain infarclion 99 FeGale Brain heDDrrha8e IDproved 200 ng x 2~
6 64 Male Brain he~Drrhage l~proYed 200 me x 8W
7 66 ~ale Brain hemorrhage ~AVhD Inproved 500 ms x 6W
8 47 Male Brain hecDrrhage Inpr w ed 300 mB x 6W
9 51 M~le Brain henDrrhage Impr w ed 200 ~B x ZW
61 Pemale Subarachnoid hemorrhageNo change 300 ng x 7W

AU~: Arteriovenous mslformalion -- I o --- 21~3514 The clinical subiects for speech disturbance were 10 cases of Broca aphasia after stroke (3 males and 7 females, age 51-65 with an average of 58.6 t/- 1.6 years).
First, without administration of droxido~a. the cllnical subiects were evaluated with standard aphasia testing (SLAT). After 300 mg of droxidopa was administered to the clinical subjects 3 times a day for 2 days, speech imProve d~or 8 of the clinical subjects, 100 mg of droxidopa was administered once a day for a sllhse~ent 2 weeks and evaluation ~as conducted using SLAT.
After 2 weeks of droxidopa ad~inistration, the average improYe~ent rates based on SLAT were as follows: ~hearing~ (short sentences, 33X; imperatives.
16%). ~readingr (short sentences, 20%; Chinese character ~ords. 10%). ~
speakingn (names. 27%; actions. i3%), "writing" (J~p~nese syllabary ~ords,2U%) and ~repeating~ (10%). 8 of the 10 cases showed impro~ed SLAT results after 2 weeks of administration. That is. one case showed improvement in nhearing. 3 cases in ~readingn. 7 cases in "speaking~, 6 cases in "writing~ and 2 uses in "
repeatingr. This indicat~s that more i~provement in speech disturbance can be expected by ad~inisterinB droxidopa for a long period of time.
Administration of droxidopa to these clinical subiects was stopped after 2 weeks. As a result. speech was totally lost in 2 cases. SubsequentlY~
administration of droxidopa was stopped twice and. in one case. speech was tDtallY lost every time administration was stopped and restored when administration was resumed. This indicates that there is a close relationship between speech improvement and administration of droxidopa. No serious side-effect was observed in the clinical subjects.
Droxid~pa has already been connercially available in Japan. and the following is reported regarding its safety.
(A) Acute toxicity (LD50) is shown in ~able 3.

213351~

- TABLE 3 Acule ~oxicily results (ID5Q ~/kg) AdmiDislralioll Mic~ ICR slrain Rats. SD s~rain beagle dogs rhesus ~onkeys ~ia ~lale ~e~le Male ~en~le Male PeD~le Male ~e~ale Oral >10000 >10000 >10000>10000 >5000 >500~ >5000 >5KX) H~ c >lOOOD >10000 84 95 Intravenous ~lCO >100 16-20 19 2~3351~

As for general symptoms. reduced voluntary motions, deeP breathing and bradypnea were observed with mice and rats, but no abnormal symptom was observed with dogs and rhesus monkeys.
(B) Subacute toxicity testing 60, 3~1 1,500 mg/kg/day was orally administered to SD rats, 200. 600, ~ 000 mg/kg/daY was orally administered to beagle dogs, and 300, 1,00~, 3.000 mg/kg/day was orallY administered to rhesus monkeYs consecutivelY for 3 months.
As a result, for dogs and nonkeys, no abnormality was observed in various observations and testing evaluations. For the rats, suppressed voluntary motions, necrosis of kidney uriniferous tubuli, necrosis of cardiac muscles, etc. were observed with 60 mg/kg/day and higher. Suppression of weight increases and such were observed with 300 mg/kg/day and higher. Drooling was obseryed with 1,500 mg/kg/day.
~C) Chronic toxicitY testing 10, 30, 100. 300 mg/kg/day was orally administered to SD rats, and 125, 500, 2,000 mx/kg/day was orally administered to beagle dogs consecutively for 12 months. As a result, for dogs, no abnorn~lity was observed in various observations and testing evaluations. For the rats, suppression of weight increases, an increase in thymus ~eight, necrosis of kidney uriniferous tubuli, degeneration of kidney glomeruli, etc. were observed with 30 mg/kg/da~ and higher, and drooling, myocarditis and calcification of cardiac muscles, etc.
-were obse~ved with 100 mæ/kg/day and higher.
(D) Procreation testing (I) Pre-pJe~n~lcY and early p.e~ c~ adninistration testing 60, 200. 600 mg/kg/das~ was orally administered to SD rats (male and female) consecutively. As a result, no influence was observed on the ~ating rate, conception rate, nidation number, embryo/neonate death, teratogenic actions or _ 2133~1~

fetal development.
(2) Organ forming period administration testing 6a, 200, 600 mg/kg/day was orally ad~inistered to SD rats consecutively. As a result, lower body weiBhts of fetuses and an increase in the occurrence of undulating ribs were obse~Yed with 200 mg/kg or higher. However. theY were within the range in which they can be restored after birth No other influence was observed. 30, 100, 300 mg/kg/day was orally administered to rabbits consecutively. As a result, no influence on the rabbits was observed (3) Perinatal and lactation perlod administration testing 6Q 200, 600 mg/kg/day was orally administered to SD rats consecutivelY. As a result, shortening of the pregnancY period was observed with 600 mg/kg, and suppression of neonatal development after birth was observed with 60 mg/kg or higher. No other influence was o~served.
(E) AntigenicitY testing Endodermoreaction. systemic anaphylaxis reaction, PCA reaction and intra-gel sedimentation reaction testing on guinea pigs (Hartley strain, male) yielded negative results.
(F) ~utagenicity testing Back mutation testing USiDg microorganisms, chromosome abnormality testing using cultured cells and micronucleus testing on mice were conducted and no mutagenicity was observe~

Claims (43)

1. The use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance.
2. The use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance.
3. The use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke or head trauma.
4. The use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
5. The use of a mixture of a peripheral decarboxylase inhibitor and a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance.
6. The use of a mixture of a peripheral decarboxylase inhibitor and a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance.
7. The use of a mixture of a peripheral decarboxylase inhibitor and a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke or head trauma.
8. The use of a mixture of a peripheral decarboxylase inhibitor and a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
9. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance.
10. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance.
11. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke or head trauma.
12. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
13. The use as claimed in claim 5 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
14. The use as claimed in claim 6 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
15. The use as claimed in claim 7 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
16. The use as claimed in claim 8 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
17. The use as claimed in claim 9 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
18. The use as claimed in claim 10 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
19. The use as claimed in claim 11 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
20. The use as claimed in claim 12 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
21. The use of a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance.
22. The use of a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance.
23. The use of a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke or head trauma.
24. The use of a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
25. The use of a mixture of a peripheral decarboxy-lase inhibitor and a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance.
26. The use of a mixture of a peripheral decarboxy-lase inhibitor and a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance.
27. The use of a mixture of a peripheral decarboxy- +
lase inhibitor and a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke or head trauma.
28. The use of a mixture of a peripheral decarboxy-lase inhibitor and a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof for motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
29. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L-threo-DOPS
or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor disturbance.
30. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L-threo-DOPS
or a pharmaceutically-acceptable acid-addition-salt thereof for treating speech disturbance.
31. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L-threo-DOPS
or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke or head trauma.
32. The use of a preparation containing a peripheral decarboxylase inhibitor and the sequential or simultaneous use of a pharmaceutically-effective amount of L-threo-DOPS
or a pharmaceutically-acceptable acid-addition-salt thereof for treating motor or speech disturbance due to stroke caused by subarachnoid hemorrhage, brain infarction or brain hemorrhage, or head trauma.
33. The use as claimed in claim 25 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
34. The use as claimed in claim 26 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
35. The use as claimed in claim 27 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
36. The use as claimed in claim 28 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
37. The use as claimed in claim 29 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
38. The use as claimed in claim 30 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
39. The use as claimed in claim 31 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
40. The use as claimed in claim 32 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
41. A pharmaceutical composition comprising a peripheral decarboxylase inhibitor, a pharmaceutically-effective amount of L- or DL-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof, and a pharmaceutically-acceptable carrier.
42. A pharmaceutical composition comprising a peripheral decarboxylase inhibitor, a pharmaceutically-effective amount of L-threo-DOPS or a pharmaceutically-acceptable acid-addition-salt thereof, and a pharmaceutically-acceptable carrier.
43. The pharmaceutical composition of claims 41 or 42 wherein said peripheral decarboxylase inhibitor is benserazide or carbidopa.
CA002133514A 1994-07-05 1994-10-03 Restorative neuropharmacological agent for motor and speech disturbance Abandoned CA2133514A1 (en)

Applications Claiming Priority (2)

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JPHEISEI6-177444 1994-07-05
JP17744494A JP3764179B2 (en) 1994-07-05 1994-07-05 Function / function-improving agent for exercise / consciousness

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CA2133514A1 true CA2133514A1 (en) 1996-01-06

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JP (1) JP3764179B2 (en)
CA (1) CA2133514A1 (en)

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US20060105036A1 (en) 2003-05-12 2006-05-18 Stephen Peroutka Threo-dops controlled release formulation
US8158149B2 (en) * 2004-05-12 2012-04-17 Chelsea Therapeutics, Inc. Threo-DOPS controlled release formulation
WO2005025561A1 (en) * 2003-09-04 2005-03-24 Synergia Pharma, Inc. Compositions and methods for orthostatic intolerance
WO2005084330A2 (en) * 2004-03-02 2005-09-15 Synergia Pharma, Inc. Compositions and methods for treating nasal congestion
ES2571730T3 (en) * 2006-06-28 2016-05-26 Lundbeck Na Ltd Pharmaceutical compositions comprising droxidopa
US20090203658A1 (en) * 2007-01-08 2009-08-13 Duke University Neuroactive steroid compositions and methods of use therefor
NZ579368A (en) * 2007-03-09 2012-03-30 Chelsea Therapeutics Inc Droxidopa and pharmaceutical composition thereof for the treatment of fibromyalgia
AU2008248382B2 (en) * 2007-05-07 2013-07-18 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders, or attention deficit disorders
JP5880913B2 (en) 2011-05-17 2016-03-09 三郎 佐古田 Treatment for trunk symptoms (postural reflex abnormalities) in Parkinson's disease

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WO2015006315A1 (en) 2013-07-08 2015-01-15 Auspex Pharmaceuticals, Inc. Dihydroxyphenyl neurotransmitter compounds, compositions and methods
EP3611159A1 (en) 2013-07-08 2020-02-19 Auspex Pharmaceuticals, Inc. Dihydroxyphenyl neurotransmitter compounds, compositions and methods

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JP3764179B2 (en) 2006-04-05
US5656669A (en) 1997-08-12

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