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`~INTERNATIONAL FILING DATE
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`PT/JP2003/010490
`TITLE OF INVENTION
`AGENT FOR TREATMENT OF SCHIZOPHRENIA
`
`PRIORITY DATE CLAIMED
`22 August 2002
`
`APPLICANT(S) FOR DO/EO/US
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`Mitsutaka NAKAMURA; Masaaki OGASA; and Shunsuke SAMI
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`PT/JP2003/01 0490
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`FORM PT0-1390 (REV 12-2004)
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`page 2 of 2
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`(
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`10/525021
`DT12 Rec'«< PCTIPTO f 8 FEB 2005
`
`1
`
`DESCRIPTION
`
`AGENT FOR TREATMENT OF SCHIZOPHRENIA
`
`5
`
`TECHNICAL FIELD
`
`1 o
`
`15
`
`The present invention relates to a novel method for treatment of
`
`schizophrenia and a novel therapeutic agent used therein. More
`
`particularly, the present invention relates to a method for improving
`
`schizophrenia without being accompanied by extrapyramidal symptoms
`
`by orally administering a prescribed dose of a specific bicycloheptane(cid:173)
`
`dicarboximide derivative once a day, and a therapeutic agent used in
`
`said method.
`
`BACKGROUND ART
`
`Schizophrenia (split personality) is a kind of endogenous
`
`psychosis, and it is developed mainly during adolescence, and after a
`
`chronic course, the personality of patient is progressively decayed, and
`
`some of patients may culminate in a mental decay. The symptoms of
`
`this disease are, for example, positive symptoms often observed during
`
`20
`
`the early stage of the disease such as hallucination, delusion, etc., or
`
`negative symptoms such as apathy and withdrawal, or cognitive
`
`dysfunction such as impairments of concentration and learning abilities,
`
`etc. Moreover, there are other symptoms such as depression, anxiety,
`
`etc. as related symptoms thereof.
`
`25
`
`Medication is mainly employed in the treatment of schizophrenia,
`
`but the treatment of schizophrenia should be continued for a long time,
`
`and even though schizophrenia is once healed, there is a large risk of
`
`reoccurring of schizophrenia after drug withdrawal so that it is
`
`necessary to continue the medication forever. Therefore, any side
`
`30
`
`effects of medication may always be serious problems, and based on
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`' ...
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`2
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`this perspective, it. has been desired to develop a medicine being
`
`suitable for prolonged medication.
`
`The agents for treatment of schizophrenia are various
`
`medicaments such as ones classified in the category of antipsychotic,
`
`5
`
`for example, phenothiazine derivatives (e.g., chlorpromazine, methox:y(cid:173)
`
`promazine, etc.}, thioxanthin derivatives having a similar structure to
`
`phenothiazine (e.g., chlorprothixene, flupentixol, etc.},- benzamide
`
`derivatives (e.g., sulpiride, sultopride, etc.), thienodiazepine derivatives
`
`(e.g., clotiazepam, etizolam, etc.), and further butyrophenone derivatives
`
`10
`
`(e.g., haloperidol, triperidol, etc.), diphenylbutylamine derivatives (e.g.,
`
`pimozide, etc.), etc.
`
`However, phenothiazine derivatives, phenothiazine analogues,
`
`and butyrophenone derivatives may cause serious side effects of
`
`extrapyramidal symptoms showing parkinsonism such as the stiff gait
`
`15
`
`of skeletal muscles, tremor of muscles, lack of facial expression,
`
`salivation, etc.
`
`Further, diphenylbutylamine derivatives may cause
`
`extrapyramidal symptoms in addition to insomnia.
`
`In addition, these
`
`conventional antipsychotics may be effective on only some of symptoms
`
`among positive symptoms, negative symptoms, cognitive dysfunctions of
`
`20
`
`schizophrenia, and there has been no drug being effective on all of these
`
`symptoms.
`
`Therefore, it has been desired to develop a safe medicament
`
`which exhibits an excellent effect on various schizophrenia as an
`
`antipsychotic without causing side effects such as extrapyramidal
`
`25
`
`symptoms.
`
`On the other hand, it has been known that the imide derivative
`
`of the following formula, which was found by the co-workers of the
`
`present inventors, may be useful as an antipsychotic (c.f,, neuroleptic
`
`agent, antiaxiety, etc.), especially as an agent for treatment of
`
`30
`
`schizophrenia, senile insanity, manic depressive psychoses, and
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`3
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`nervous breakdown (USP 5,532,372).
`
`I\.
`Z-0-N
`G-Ar
`\ _ /
`
`wherein Z is
`
`5
`
`Dis a group of the formula: -{CH2)p-A-(CH2)q-,
`
`"
`
`N-
`
`G':t /
`
`"
`
`CH-
`
`or /
`
`, etc., and
`
`Ar is an aromatic group, or an aromatic heterocyclic group, etc.
`
`DISCLOSURE OF INVENTION
`
`10
`
`The present inventor has intensively studied on a series of imide
`
`derivatives with respect to many aspects including a use and a dose
`
`thereof in order to find a novel agent for treatment of schizophrenia,
`
`which may exhibit an excellent effect in the treatment of schizophrenia
`
`and have no side effect such as extrapyramidal symptoms, which are
`
`15
`
`often observed in many conventional antipsychotics, and can safely be
`
`administered for a long time. As a result, the present inventors have
`
`found that ( 1R,2S,3R,4S)-N-[( 1R,2R)-2-(4-( 1,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptane(cid:173)
`
`dicarboximide of the following formula:
`
`N
`
`~ !::! 0
`-
`-=
`=Ho
`H
`
`.
`
`r-\
`
`N,
`
`(1)
`
`HH
`
`\ _ J
`
`-
`~ ~
`
`20
`
`or a pharmaceutically acceptable salt thereof such as a hydrochloride
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`4
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`thereof is effective for relieving the wide-ranging symptoms of
`
`schizophrenia, and may treat schizophrenia quite safely without being
`
`accompanied by extrapyramidal symptoms by orally administering a
`
`prescribed dose thereof once a day.
`
`5
`
`Namely, the present invention provides a method for treatment
`
`of schizophrenia without being accompanied by extrapyramidal
`
`symptoms by orally administration of a prescribed amount of
`
`( 1R,2S,3R,4S)-N-[( 1R,2R)-2-[4-( 1 ,2-benzoisothiazol-3-yl)-1-piperazinyl(cid:173)
`
`methyl]-1-cyclohexylmethyl]-2,3-bicyclo[2 .2 .1]heptanedicarboximide of
`
`10
`
`the above formula ( 1) or a pharmaceutically acceptable salt thereof once
`
`a day, and further provides an agent for treatment of schizophrenia
`
`which is used in said method.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`15
`
`Fig. 1 is a graph showing the change with time in scores of Brief
`
`Psychiatric Rating Scale: BPRS, which are indexes for the effects on
`
`schizophrenia, of the active compound of the present invention,
`
`( 1R,2S,3R,4S)-N-[( 1R,2R)-2-[4-( 1 ,2-benzoisothiazol-3-yl)-1-piperazinyl(cid:173)
`
`methyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide
`
`20
`
`hydrochloride and placebo in the double blind clinical trial.
`
`DETAILED DESCRIPTION OF INVENTION
`
`As shown in Examples as described hereinafter, when orally
`
`administering a prescribed dose of ( 1R,2S,3R,4S)-N-[( 1R,2R)-2-[4-( 1,2-
`
`25
`
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2.1]heptanedicarboximide hydrochloride once a day for 6
`
`weeks to the patients with schizophrenia in the acute exacerbation, the
`
`present inventors have found that the excellent effects on the wide(cid:173)
`
`ranging symptoms were obtained, and surprisingly, any extrapyramidal
`
`30
`
`symptoms as observed in the conventional antipsychotics were hardly
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`5
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`observed, especially, abnormal electrocardiogram which progresses to
`
`sudden death is not recognized, and hence, that this compound may be
`
`quite safely used in the treatment of schizophrenia.
`
`Namely, the present invention provides a novel method for
`
`5
`
`treatment of schizophrenia improving a wide-ranging schizophrenia
`
`including positive symptoms, negative symptoms, and cognitive
`
`dysfunction, especially positive symptoms and negative symptoms,
`
`without being accompanied by extrapyramidal symptoms which
`
`comprises orally administering a prescribed dose of ( 1R,2S,3R,4S)-N-
`
`10
`
`[{1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclo-
`
`hexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide of the above
`
`formula (1) or a pharmaceutically acceptable salt thereof, especially a
`
`hydrochloride thereof, to a patient with schizophrenia once a day.
`
`The present invention also provides a novel agent for treatment
`
`15
`
`of such schizophrenia.
`
`According to the present invention, excellent improving effects
`
`on the wide-ranging symptoms of schizophrenia may be obtained by
`
`orally administering ( 1R,2S,3R,4S)-N-[( 1R,2R)-2-[4-( 1,2-benzoisothiazol-
`
`3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]-
`
`20
`
`heptanedicarboximide or a pharmaceutically acceptable salt thereof, for
`
`example, a hydrochloride, at a daily dose of 5 mg to 120 mg, preferably
`
`at a daily dose of 10 mg to 100 mg, more preferably at a daily dose of 20
`
`mg to 80 mg, once a day. Further, in the therapeutic method of the
`
`present invention, side effects such as extrapyramidal symptoms such
`
`25
`
`as parkinsonism, dyskinesia, akathisia, etc., abnormal electro(cid:173)
`
`cardiogram, hepatic dysfunction are hardly observed, and hence, the
`
`present method may be quite safely used and suitable for a prolonged
`
`medication.
`
`Besides, when the present method is applied to a patient with
`
`30
`
`schizophrenia in chronic phase, the above active compound should
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`6
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`preferably be administered to said patient for a long time at a dose as
`
`low as possible, and in such a case, the daily dose of the active
`
`compound is in the range of 5 mg to 80 mg, preferably in the range of 5
`
`mg to 60 mg, more preferably in the range of 10 mg to 40 mg, and it is
`
`5
`
`orally administered once a day.
`
`The therapeutic agent used in the method for treatment of
`
`schizophrenia of the present invention is in the form of an oral
`
`preparation, which contains the compound of the above formula (1) or a
`
`pharmaceutically acceptable salt thereof, especially (1R,2S,3R,4S)-N-
`
`10
`
`[( 1R,2R)-2-[4-( 1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclo(cid:173)
`
`hexylmethyl]-2 ,3-bicyclo[2 .2. 1 ]heptanedicarboximide hydrochloride in
`
`an amount of 5 mg to 120 mg; preferably in an amount of 10 mg to 100
`
`mg, more preferably in an amount of 20 mg to 80 mg per a single
`
`dosage unit. The oral preparation includes, for example, tablets,
`
`15
`
`granules, fine granules, powders, capsules, syrups, etc. These
`
`preparations should be in the form of a preparation for administration
`
`once a day.
`
`The above preparations may be prepared by a conventional
`
`method by using a conventional pharmaceutically acceptable carrier
`
`20
`
`which is usually used in the preparation of a conventional
`
`pharmaceutical formulation, for example, excipients such as lactose,
`
`white sugar, glucose, starch, calcium carbonate, kaolin, talc, crystalline
`
`cellulose, silicic acid, etc., binders such as water, ethanol, gelatin,
`
`carboxymethylcellulose, shellac, methylcellulose, gum arabic,
`
`25
`
`tragacanth powder, polyvinylpyrrolidone, etc., disintegrating agents
`
`such as sodium arginate, agar powder, laminaran powder, sodium
`
`hydrogen carbonate, polyoxyethylenesorbitan fatty acid esters, sodium
`
`laurylsulfate, stearic acid monoglyceride, etc., lubricants such as
`
`purified talc, stearate, boric acid powder, polyethyleneglycol, etc.
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`7
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`EXPERIMENTS
`
`The method for treatment of the present invention and the
`
`effects thereof are illustrated in more detail by Experiments as
`
`described hereinafter.
`
`5
`
`The active compound SM-13496 used in Experiments means
`
`( 1R,2S,3R,4S)-N-[( 1R,2R)-2-[4-( 1,2-benzoisothiazol-3-yl)-1-piperazinyl(cid:173)
`
`methyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide
`
`hydrochloride, and the meanings of the abbreviations used in
`
`Experiments are as follows.
`
`10
`
`DSM-IV:
`
`Diagnostic and Statistical Manual of Mental Disorders, 4th
`
`CGI-S:
`
`CGI-I:
`
`AIMS:
`
`EPS:
`
`LOCF:
`
`BAS:
`
`SAS:
`
`15
`
`20
`
`ed.
`
`Clinical Global Impressions scale-Severity of Illness
`
`Clinical Global Impressions scale-Improvement
`
`Abnormal Involuntary Movement Scale
`
`Extrapyramidal symptoms
`
`Last Observation Carried Forward
`
`(LOCF Analysis: a method of using last not-missing data in
`
`cases of dropouts)
`
`Barnes Akathisia Scale
`
`Simpson-Angust Rating Scale
`
`(Rating Scale For Extrapyramidal Reactions)
`
`PANSS:
`
`Positive and Negative Syndrome Scale
`
`(Rating Scale For Positive · Negative symptoms)
`
`25
`
`Experiment 1
`
`First Stage Phase II Clinical Trial
`
`( 1)
`
`Test method
`
`According to the procedures as shown in Table 1 as described
`
`below, the placebo-controlled double blind experiment was done on 149
`
`30
`
`patients with schizophrenia in the acute exacerbation phase at 15
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`8
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`facilities in USA. The efficacy and safeness were studied when SM-
`
`13496 at a dose of 40 mg or 120 mg, or a placebo was orally
`
`administered once a day for 6 weeks after placebo washout.
`
`Table 1
`Name of
`Clinical Trial
`
`Purpose
`
`Subjects
`
`Design of
`Clinical Trial
`Dosage and
`Administration
`route
`
`A double-blind, randomized, fixed dose, placebo(cid:173)
`controlled, parallel-group, 6-week, efficacy, safety, and
`tolerability study of two dose levels of SM -13496 in
`patients with schizophrenia by DSM-IV criteria who are
`experiencing an acute exacerbation of symptoms
`The efficacy and safety on patients with schizophrenia
`in the acute exacerbation phase (DSM-IV criteri~) were
`studied in the placebo-controlled, parallel-group,
`double-blind test.
`Selection criteria:
`1) Patients with scchizophrenia determined according to
`DSM-IV criteria who are experiencing an acute
`exacerbation of symptoms
`2) Patients having 42 or more ofExtracted-BPRS Score
`as well as 4 or more of CGI -S Score
`3) Patients having less than 2 of Simpson-Angus Score
`as well as less than 3 of AIMS Score
`4) Patients suffering from schizophrenia for more than 1
`year
`5) Males and females aged 18-64 years
`
`Factors for patient exclusion:
`1) Patients with treatment-resistant schizophrenia
`2) Patients being taking depot injections before fmishing
`the therapy cycle
`3) Patients having a strong suicidal ideation
`4) Patients with Parkinson's disease, Alzheimer disease,
`drug addiction, convulsive disorders, epilepsy
`5) Pregnant women and any women having a possibility
`of pregnancy, and lactating women
`6) Patients having drug hypersensitivity
`7) Any patients who are examined not to be suitable as
`subjects by principal investigator
`Placebo-controlled, randomized, comparison with
`parallel-group, double-blind
`Oral administration of the test compound at a dose of
`40mg/ day, 120mg/ day or a placebo once a day for 6
`weeks
`Washout with placebo for one week (at least for 3 day)
`Hospitalization during the washout period and two
`weeks after medication
`
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`9
`
`..
`
`Combined
`Drug and
`Combination
`Therapy
`
`1)
`
`2)
`
`Number of
`subjects
`
`Evaluation
`Items
`
`Another antipsychotic is not administered. When
`another antipsychotic is taken, then it is necessary
`to set up a washout period before the trial at least 3
`days for oral drug or for one therapy cycle for depot
`injection.
`In case of onset of extrapyramidal symptoms, then
`the administration of an antiparkinson agent is
`allowed.
`3) In case of onset of insomnia, lorazepam is used.
`In the planning stages:132 subjects (each 44 subjects
`for the placebo-treated group, the 40 mg-treated group
`and the 120 mg-treated group)
`After the completion of the trial: 149 subjects (50
`subjects for the placebo-treated group, 50 subjects for
`the 40 mg-treated group, and 49 subjects for the 120
`mg-treated group)
`Efficacy: PANSS, Extracted-BPRS, CGI-S/I
`Safety: EPS Rating scale (Simpson-Angus, Barnes,
`AIMS}, vital signs (body temperature, blood pressure,
`pulse), 12-lead electrocardiogram, laboratory test
`[hematologic test, biochemical test of blood, prolactin,
`urine test], psychosomatic conditions, eyeground·slit(cid:173)
`lamp microscopy, adverse event
`Test results:
`
`· (2)
`
`1)
`
`(i)
`
`Evaluation of efficacy:
`
`The data by BPRS and PANSS (LOCF), and CGI-S and CGI-1 at
`
`the end of the trial are shown in Table 2 and Table 3, respectively. As
`
`5
`
`is shown in Table 2 and Table 3, the reductions in the scores at the end
`
`of the trial (6 weeks after the administration) from those prior to the
`
`administration in the groups treated by SM-13496 40 mg or 120 mg are
`
`statistically significant as compared to that in the placebo-treated group
`
`with respect to BPRS, CGI-I and CGI-S evaluations. With respect to
`
`10
`
`PANSS evaluation, the reduction in the score at the end of the
`
`experiment in the SM-13496 120 mg-treated group is statistically
`
`significant as compared to that in the placebo-treated group,. which
`
`means the psychotic manifestations are improved by SM-13496.
`
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`10
`
`Table 2
`
`Dose
`
`(No. of
`Subjects)
`
`Rating
`scale
`
`BPRS
`Total
`Score
`
`PANSS
`Total
`Score
`
`Placebo
`(45)
`
`SM-13496 40 mg
`(47)
`
`SM-13496 120 mg
`(44)
`
`Average Average (SO)
`(SO)
`
`p value41
`
`Average
`(SO)
`
`p value#
`
`-4.0 (8.45)
`
`-5.8
`(14.06)
`
`-10.0
`(12.79)
`
`-14.1
`
`(23.10)
`
`0.014
`
`-11.3 (8.89)
`
`0.003
`
`0.063
`
`-17.4
`(15.70)
`
`0.010
`
`#:Two-sided Dunnett's t-test (comparison between the groups treated by each
`dose and the placebo-treated group)
`Covariance analysis using faculty and Groups as factors and the values before
`administration as covariate
`Table 3
`
`Dose
`
`Placebo
`
`SM-13496 40 mg
`
`SM-13496 120 mg
`
`Rating
`Scale
`
`CGI-S
`
`CGI-I
`
`Average
`(SO)
`
`Average
`(SO)
`
`p value#
`
`(n=41)
`
`(n=41)
`
`0.0 (0.77)
`
`-0.7 (1.12)
`
`(n=45)
`
`(n=47)
`
`4.0 (1.41)
`
`3.2 (1.56)
`
`0.004
`
`0.013
`
`Average
`(SO)
`
`(n=40)
`
`-0.8 (1.03)
`
`(n=42)
`
`3.0 (1.29)
`
`p value#
`
`0.002
`
`0.005
`
`#:Two-sided Dunnett's t-test (comparison between the groups treated by each
`dose and the placebo-treated group)
`Covariance analysis using faculty and Groups as factors and the values before
`administration as covariate
`Further, the appended Fig. 1 shows the changes in BPRS total
`(ii)
`
`score (LOCF). As is shown in Fig. 1, the BPRS scores in the SM-13496-
`
`5
`
`treated groups are statistically significantly reduced from those of prior
`
`to the administration as compared to that in the placebo-treated group
`
`at the 2 weeks or later (p<O.OS).
`
`(iii)
`
`The ratio of the patients of which the BPRS reduction at the end
`
`of the experiment is 20 °/o or more, or the patients who showed 1 or 2 of
`
`10
`
`CGI-I, those patients are considered as responder, is shown in Table 4.
`
`As is apparent from Table 4, there was a statistically significant
`
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`11
`
`..
`
`difference between the SM-13496 40 mg- or 120 mg-treated group and
`
`the placebo-treated group.
`
`Table 4
`
`Dose
`
`(No. of
`Subjects)
`
`Placebo
`
`SM-13496 40 mg
`
`SM-13496 120 mg
`
`(45)
`
`(47)
`
`(44)
`
`Number
`
`Number
`
`p value*
`
`Number
`
`p value*
`
`Responder
`
`10
`
`26
`
`0.002
`
`22
`
`0.007
`
`(comparison
`the faculties
`test adjusting
`#: Cochran-Mantel-Haenszel
`between the groups treated by each dose and the placebo-treated group)
`2)
`Evaluation of Safety:
`
`5
`
`(i)
`
`Adverse events observed in 10 °/o or more of the patients are
`
`shown in Table 5.
`
`Table 5
`
`Number of Subjects
`
`50
`
`50
`
`49
`
`Placebo
`
`40mg
`
`120 mg
`
`Number of subjects showing adverse
`events (0/o)
`
`Number of subjects showing serious
`adverse events (o/o)
`
`Number of subjects who drop out from
`the trial due to adverse events (o/o)
`Occurrence of Adverse events (o/o)
`
`Digestive disturbance
`Nausea
`
`Headache
`
`Akathisia
`
`Free-floating vertigo (excluding
`rotatory vertigo)
`
`Suppression
`
`Drowsiness
`
`Exacerbation of schizophrenia
`
`36 (72)
`
`40 (80)
`
`38 {78)
`
`3 (6)
`
`3 {6)
`
`3 (6)
`
`2 (4)
`
`6 (12)
`
`6 (12)
`
`6 (12)
`
`2 (4)
`
`5 (10)
`
`0 (0)
`
`3 (6)
`5 (10)
`
`2 (4)
`
`5 (10)
`
`4 (8)
`
`5 (10)
`
`8 (16)
`
`4 (8)
`
`6 (12)
`
`9 (18)
`
`4 (8)
`
`2 (4)
`
`2 (4)
`
`11 {22)
`
`3 (6)
`
`7 (14)
`
`5 (10)
`7 (14)
`
`5 (10)
`
`1 (2)
`
`Subject having multiple adverse events was accounted as 1.
`As is shown in Table 5, 114 subjects among 149 subjects (77 o/o)
`
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`12
`
`showed adverse events, but most of them were mild or moderate ones.
`
`The number of subjects who dropped out from the trial due to the
`
`adverse events was higher in both of the groups treated by two doses of
`
`SM-13496 than in the placebo-treated group.
`
`5
`
`The main adverse events are suppression, nausea, headache,
`
`akathisia, and free-floating vertigo (excluding rotatory vertigo). The
`
`ratio of the subjects showing suppression was 10 o/o, 18 °/o, 14 °/o in the
`
`placebo-treated group, the SM-13496 40 mg-treated group, and the SM-
`
`13496 120 mg-treated group, respectively.
`
`In the SM-13496 120 mg-
`
`10
`
`treated group, nausea was more observed as compared to the other
`
`groups, but digestive disturbance was less observed than in the
`
`placebo-treated group. Exacerbation of schizophrenia was less
`
`observed in the SM-13496 40 mg- and 120 mg-treated groups (4 °/o and
`
`2 °/o, respectively) than in the placebo-treated group (10 °/o). Akathisia
`
`15
`
`was observed only in the SM-13496 treated groups, i.e., 8 o/o and 14 o/o
`
`in the 40 mg-treated group and in the 120 mg-treated group,
`
`respectively. The occurrence of the adverse events in the groups
`
`treated by SM-13496 were the same as that in the placebo-treated
`
`group. Either body weight gain, bulimia, impotence, erectile
`
`20
`
`dysfunction or convulsion was not observed.
`
`(ii)
`
`The serious adverse events observed in the above phase II
`
`clinical trial are shown in Table 6 as described below.
`
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`13
`
`Table 6
`
`Number of Subjects
`
`Total (o/o)
`
`Placebo
`
`50
`
`4 (8)
`
`Occurrence of Serious Adverse Events (o/o)
`
`Exacerbation of
`paranoia
`
`Psychosis aggravated
`
`Exacerbation of
`schizophrenia
`
`Paranoid
`schizophrenia
`
`0 (0)
`
`0 (0)
`
`4 (8)
`
`0 (0)
`
`40mg
`
`50
`
`3 (6)
`
`1 (2)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`120 mg
`
`49
`
`2 (4)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`As is shown in Table 6, the serious adverse events were observed
`
`in 4 cases of the placebo-treated group, 3 cases of the SM-13496 40
`
`mg-treated group and 2 cases of the SM-13496 120 mg-treated group,
`
`5
`
`but the relationship to the tested medicament was denied.
`
`(iii)
`
`Further, the side effects observed in this clinical trial are listed
`
`in the following Table 7.
`
`Table 7
`
`Number of Subjects
`Occurrence of side
`effects {o/o)
`
`Mental disturbance
`
`Restlessness
`Psychosis aggravated
`Agitation
`Agitation aggravated
`Anxiety aggravated
`Insomnia
`Exacerbation of
`insomnia
`Nightmare
`
`Placebo
`
`50
`
`40mg
`
`50
`
`120 mg
`
`49
`
`22 (44)
`
`33 (66)
`
`35 (71)
`
`0 (0)
`0 (0).
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`0 (0)
`0 (0)
`
`0 (0)
`1 (2)
`1 (2)
`
`0 (0)
`
`0 (0)
`
`1 (2)
`2 (4)
`1 (2)
`2 (4)
`0 (0)
`1 (2)
`
`1 (2)
`
`1 (2)
`
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`14
`
`Metabolic disturbances and nutritional disturbance
`
`Anorexia
`Decrease in appetite
`
`1 (2)
`1 (2)
`
`Disturbance in Skin and Hypodermis
`
`Pruritus
`
`Infection and parasitosis
`
`Tinea pedis
`Extemal otitis
`Parotiditis
`Urinary tract
`infection
`Vascular diseases
`
`Flushing
`Hot flashes
`
`1 (2)
`
`0 (0)
`0 (0)
`1 (2)
`
`0 (0)
`
`1 (2)
`0 (0)
`
`1 (2)
`1 (2)
`
`0 (0)
`
`0 (0)
`1 (2)
`0 {0)
`
`1 (2)
`
`0 (0)
`0 (0)
`
`Disturbance in respiratory organ, chest and mediastinum
`
`Laryngopharynx pain
`Breathing difficulty
`
`Heart problems
`
`Sinus tachycardia
`Palpitation
`
`Gastroenteric disturbance
`
`Nausea
`Vomiting
`Constipation
`Diarrhea
`Loose stools
`Tongue disturbance
`Dyspepsia
`Flatulence
`Dry mouth
`Salivary
`hypersecretion
`Abdominal pain
`
`0 (0)
`0 (0)
`
`0 (0)
`0 (0)
`
`2 (4)
`0 (0)
`1 (2)
`3 (6)
`0 (0)
`0 (0)
`2 (4)
`0 (0)
`1 {2)
`
`1 {2)
`
`2 (4)
`
`1 (2)
`0 (0)
`
`0 (0)
`0 (0)
`
`4 (8)
`2 (4)
`2 (4}
`3 (6)
`0 (0)
`1 (2)
`3 (6)
`1 (2)
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`1 (2)
`
`0 (0)
`
`1 (2)
`0 (0)
`0 (0)
`
`0 (0)
`
`0 (0)
`1 (2)
`
`0 (0)
`1 (2)
`
`1 (2)
`1 (2)
`
`9 (18)
`3 (6)
`0 (0)
`0 (0)
`1 (2)
`0 (0)
`2 (4)
`0 (0)
`0 (0)
`
`0 (0)
`
`0 (0)
`
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`15
`
`Total disability and local condition
`
`Fatigue
`Fatigue aggravated
`Hot sensation
`Sleepiness
`
`Netvous system disorder
`
`Suppression
`Akathisia
`Free-floating vertigo
`(excluding rotatory
`vertigo)
`Drowsiness
`Headache
`Extrapyramidal
`disease
`Tremor
`Akathisia aggravated
`Dystonic reaction
`Anarthria
`Glossoplegia
`Cogwheel rigidity
`Trismus
`
`3 (6}
`0 (0)
`1 (2)
`1 (2)
`
`3 (6)
`0 (0)
`
`0 (0)
`
`2 (4)
`3 (6)
`
`0 (0)
`
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`1 (2)
`0 (0)
`0 (0)
`
`3 (6)
`1 (2)
`0 (0)
`1 (2)
`
`9 (18)
`4 (8)
`
`5 (10)
`
`4 (8)
`6 (12)
`
`1 (2)
`
`3 (6)
`1 (2)
`1 (2)
`0 {0)
`0 (0)
`0 (0)
`0 (0)
`
`Musculoskeletal system and connective tissue disorder
`
`Muscle stiffness
`Myalgic pain
`Cetvical rigidity
`Articular rigidity
`Melalgia
`Heavy feeling
`
`1 (2)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`2 (4)
`0 (0)
`1 (2)
`1 (2)
`0 (0)
`1 (2)
`
`1 (2)
`0 (0)
`0 (0)
`2 (4)
`
`7 (14)
`7 (14)
`
`5 (10)
`
`5 (10)
`1 (2)
`
`3 (6)
`
`3 (6)
`0 (0)
`0 (0)
`1 {2)
`0 (0)
`1 (2)
`1 (2)
`
`1 (2)
`1 (2)
`0 (0)
`0 (0)
`1 (2)
`0 (0)
`
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`16
`
`0 (0)
`
`0 (0)
`
`1 (2)
`
`1 (2)
`
`0 (0)
`
`0 (0)
`
`Laboratory assay
`
`Increase in prolactin
`level in the blood
`Increase in creatine
`phosphokinase level
`in the blood
`Abnormal
`electrocardiogram
`Weight loss
`Increase in total
`protein
`Abnormal liver
`function tests
`
`Renal Injury and urinary disorder
`
`Polyuria
`Frequent urination
`
`Ocular disturbance
`
`Blurred