Prophylactic and therapeutic agent for attention-deficit/hyperactivity disorder

Abstract

It is already known that 1-(benzofuran-2-yl)-2-propylaminopentane or a pharmacologically acceptable acid addition salt thereof exhibits an excellent effect as an antidepressant, a psychotropic drug, an antiparkinsonian drug, and an anti-Alzheimer's disease drug. However, it has not been known at all that the compound is effective for the prevention or therapy of attention-deficit/hyperactivity disorder (ADHD). The present invention has newly found that 1-(benzofuran-2-yl)-2-propylaminopentane or a pharmacologically acceptable acid addition salt thereof is effective for the prevention or therapy of ADHD, and has been accomplished.

Claims

1. A therapeutic method for attention-deficit/hyperactivity disorder comprising administering an effective dose of 1-(benzofuran-2-yl)-2-propylaminopentane or a pharmacologically acceptable acid addition salt thereof to a patient suffering from attention-deficit/hyperactivity disorder.

2. The therapeutic method for attention-deficit/hyperactivity disorder according to claim 1, wherein said effective dose of 1-(benzofuran-2-yl)-2-propylaminopentane or a pharmacologically acceptable acid addition salt thereof is from 1 mg/day to 500 mg/day.

3. The therapeutic method for attention-deficit/hyperactivity disorder according to claim 2, wherein 1-(benzofuran-2-yl)-2-propylaminopentane is (−)-1-(benzofuran-2-yl)-2-propylaminopentane.

4. The therapeutic method for attention-deficit/hyperactivity disorder according to claim 1, wherein the 1-(benzofuran-2-yl)-2-propylaminopentane or a pharmacologically acceptable acid addition salt thereof is used in combination with one or more other therapeutic agents for attention-deficit/hyperactivity disorder selected from the group consisting of methylphenidate, atomoxetine, amphetamine, dextroamphetamine, lisdexamfetamine, guanfacine, clonidine, and bupropion.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the effects of the compound for use in the invention on the alternation rate (left) and the total arm entries (right) in SHRSP/Ezo rats in a Y-maze test.

(2) Means±standard error (n=10 to 18), * (p<0.05), ** (p<0.01) vs. vehicle (alternation rate) or total arm entries in Y1 trial. The broken lines ( - - - - ) indicate the average values of the alternation rate and the number of entries in Wistar-Kyoto (WKY) rats as genetic control animals conducted separately.

(3) FIG. 2 shows the effects of the compound for use in the invention on hyperactivity in SHRSP/Ezo rats in a 60-minute open field test.

(4) Means±standard error (n=7), * (p<0.05), ** (p<0.01) vs. vehicle. The broken lines ( - - - - ) indicate the average values of the total crossings in the indicated range of times in WKY rats conducted separately.

(5) FIG. 3 shows the effects of the compound for use in the invention on increases of the inner zone spent time in SHRSP/Ezo rats in an open field test in the upper panel and the inner zone spent times per total crossings in the lower panel.

(6) Means±standard error (n=6 to 7), * (p<0.05), ** (p<0.01) vs. vehicle. The broken lines ( - - - - ) indicate the average values of the inner zone spent times and the inner zone spent times per total crossings in the indicated range of times in WKY rats conducted separately.

(7) FIG. 4 shows the effects of the compound for use in the invention on the total arm entries (upper left), the rate of open arm entries (upper right), the open arm spent times (lower left), and the time spent in open arms/total number of arm entries (lower right) in a 10-minite elevated-plus maze test using SHRSP/Ezo rats.

(8) Means±standard error (n=8 to 9), * (p<0.05) vs. vehicle. The broken lines ( - - - - ) indicate the average values of the total number of arm entries, the rate of open arm entries, the open arm spent times, and the open arm spent times/total arm entries in WKY rats conducted separately.

(9) Y1 in FIG. 1 represents the first trial. Y2 in FIG. 1 represents the second trial. * in FIGS. 1 to 4 represents a significant level p<0.05 and ** represents a significant level p<0.01. The columns in FIGS. 1 to 4 indicate that □ is the vehicle; .square-solid. is methylphenidate at 1 mg; is BPAP at 0.01 mg/kg; is BPAP at 0.03 mg/kg; is BPAP at 0.1 mg/kg; and is BPAP at 0.3 mg/kg. Further, VEH and MPH in FIG. 4 represent vehicle (saline) and methylphenidate, respectively.

MODE FOR CARRYING OUT THE INVENTION

(10) The invention will be further described hereinafter by use of experiments, etc. It should however be noted that the invention is not limited to the following experimental examples.

Example 1

(11) 1. Experimental Method

(12) Spontaneous hypertensive rats (SHR) have been widely used as an ADHD animal model. It has become evident that SHR, established as an essential hypertensive model in 1963, exhibits behavioral similarities to the ADHD symptoms such as hyperactivity, impulsivity and inattention at the juvenile period. However, SHR do not fulfil the behavioral and pharmacological profiles of an animal model of ADHD. For instance, the ADHD-like behaviors do not show male preponderance in SHR, and the effective dose of methylphenidate is high. Although the gene and the chromosomal domain related to the ADHD-like behaviors observed in SHR have not yet been fully clarified, it has been suggested, from the analysis of the phenotype in sub-strains and congenic rats, that there is no correlation between the abnormal behavior and the hypertension. As other ADHD models, some models have been reported including neonatal rats injected 6-hydroxydopamine into the brain, DAT knockout mice, Naples high-excitability (NHE) rats. However, it cannot be said that any of these animal models has sufficient validity as an ADHD model judging from the expression of symptoms and the response to therapeutic drugs, etc.

(13) In consideration of the above, the present inventors have studied the validity as an ADHD model using the stroke-prone spontaneously hypertensive rats (SHRSP) as a sub-strain of SHR. Among others, SHRSP/Ezo rats as a sub-strain of SHRSP isolated from SHR in 1974 is considered to be an ADHD model more reflecting the clinical features of ADHD from the facts such as that behavioral pharmacological features such as hyperactivity, impulsivity, and inattention during the juvenile period, that the male preponderance on the symptom is recognized, and that the effective dose of methylphenidate is close to the clinical dose range. In this experiment, therefore, the effects of the compound for use in the invention on the ADHD-like symptoms have been evaluated behavioral-pharmacologically using SHRSP/Ezo rats.

(14) In all the tests described herein, the R configuration (−) substance hydrochloride salt of the compound for use in the invention (hereinafter referred to as “BPAP” in some cases) as the test material and methylphenidate hydrochloride (SIGMA Aldrich) as the comparative drug were dissolved in saline, diluted to a volume of 2 ml/kg before administration, and systemically administered into six-week-old male SHRSP/Ezo rats 30 minutes before behavior tests. Note that BPAP was subcutaneously (s.c.) administered, and methylphenidate was subcutaneously (s.c.) or intraperitoneally (i.p.) administered after the confirmation that there was no difference between the two routes, i.e., the s.c. and i.p. administration.

(15) 1) Evaluation of Inattentive Behavior in the Y-Maze Test

(16) The short-term working memory was evaluated as a spontaneous alternation behavior using a Y-maze (45 (length)×10 (width)×35 cm (height)). The spontaneous alternation is a behavior based on the habit of a rodent preferring to investigate a new arm of the maze rather than returning to one that was previously visited in the Y-maze. In order to select three different arms continuously, it is necessary to remember the previously visited arm. To achieve this, therefore, the short-term working memory is considered indispensable. Because the processes of the short-term working memory are closely related to an appropriate amount of attention toward achievement of the task, the short-term working memory implicates aspects of attention. Thus, the Y-maze test was carried out to evaluate the inattentive behavior in SHRSP/Ezo rats.

(17) The spontaneous alternation was measured according to the method by Sarter et al. (Psychopharmacology (Berl), 94:491-5 (1988)) using the following procedure. Under a 200-lux illuminance condition, each rat was placed in the center of the crossing point of the three arms and allowed to enter the maze arm freely for eight-minute test session, and the sequence of arm entries was recorded. The alteration behavior was defined as the consecutive entry into three arms, i.e. the combination of three different arms, with stepwise combinations in the sequence. The percentage obtained by dividing the spontaneous alternation behavior by the total number of arm entries (total arm entries) minus 2 was determined as the spontaneous alternation behavior rate (alternation rate). For example, assuming that the rat has entered the arms A, B, and C of the Y-maze in the order of ACBABACBAB, the spontaneous alternation behavior is five (ACB, CBA, BAC, ACB, and CBA), the total number of arm entries is ten, and the spontaneous alternation behavior rate is 62.5%. To consider the influence of variations in spontaneous alternation behavior rate among groups during the baseline (drug-untreated) period on the drug efficacy evaluation, the first Y-maze test was carried out three days before the drug efficacy evaluation, and grouping was performed based on the result of spontaneous alternation behavior rates in the 1.sup.st Y-maze test.

(18) 2) Evaluation of Hyperactivity in the Open Field Test

(19) The spontaneous locomotor activity in a new environment was evaluated using an open-field apparatus (90 (width)×90 (depth)×40 cm (height), 81 squares). Since an animal exposed to a new environment exhibits an exploration behaviors and rearing activities, the open field test is generally used for evaluation of the locomotor activity, emotionality, and general behaviors of animals.

(20) In this experiment, under a 200-lux illuminance condition, rats were placed in the center of the open field and allowed to move freely in the field for a 60-minute test session, and the horizontal activities (crossings: the number of squares crossed) during the exploration was analyzed by a video tracking system for behavioral experiments (LimeLight Actimetrics, USA).

(21) 3) Evaluation of Impulsivity in the Elevated-Plus Maze Test

(22) The anxiety-related behavior was evaluated using an elevated plus maze (open arm: 50 (length)×10 cm (width), enclosed arm: 50 (length)×10 (width)×40 cm (height), height above the floor: 50 cm). The device is constituted by a wall-less open arm and a wall-surrounding enclosed arm crossing each other at right angles at a height of 50 cm above the floor. An animal staying in an open arm is exposed to anxiety in the elevated wall-less open state. A normal animal therefore does not stay long in the open arm. The elevated-plus maze test reflects an equilibrium state between the approach behavior (curiosity) and the avoidance behavior driven by anxiety in an animal, and thus is generally used for the evaluation of the anxiety level of an animal. It is suggested that involvement of the anxiety level in impulsivity of ADHD patients, and thus the impulsivity is considered to embrace an aspect of having a reduction in anxiety level as the background.

(23) In this experiment, under a 200-lux illuminance condition, a rat was placed in the center of the crossing point of two sets of arms and allowed to enter freely into the maze for a ten-minute test session. The total number of arm entries (total arm entries), the time spent in open arms and the rate of open arm entries were analyzed by a video tracking system for behavioral experiments (LimeLight Actimetrics).

(24) 4) Statistics Analysis

(25) Data were represented as the means±standard errors. Student's t-test was used for the statistics analysis, and a P value below 5% was considered statistically significant.

(26) 2. Experimental Result

(27) 1) Validity of Dose of Methylphenidate, the First-Choice of Medication for ADHD, as Comparative Drug

(28) As a result of the evaluation of the spontaneous locomotor activity in the open field test, horizontal ambulatory significantly increased in SHRSP/Ezo rats at the habituated phases of 15 to 60 minutes, in comparison with Wistar-Kyoto (WKY) rats as genetic control animals. By contrast, at the exploration phase in the initial 0 to 15 minutes period, the horizontal ambulatory did not differ between SHRSP/Ezo and the WKY rats. The intraperitoneal administration of methylphenidate (0.01 to 30 mg/kg) significantly decreased the hyperactivity in SHRSP/Ezo rats at 0.01 and 0.1 mg/kg, but it did not decreased at 1 mg/kg. By contrast, the increase in spontaneous ambulatory was exacerbated with 3 and 30 mg/kg of methylphenidate.

(29) In the evaluation of the impulsivity in the elevated-plus maze test, the number of open arm entries and the open arm spent time increased in SHRSP/Ezo rats, compared with those of the WKY rats. As for the number of enclosed arm entries, however, no difference was observed between SHRSP/Ezo and the WKY rats. The intraperitoneal administration of methylphenidate (0.01 to 1 mg/kg) provided no statistically significant change for the increase in the number of open arm entries and the extension of the open arm spent time in SHRSP/Ezo rats.

(30) In the evaluation of the inattentive behavior in the Y-maze test, the spontaneous alternation behavior rate in SHRSP/Ezo rats significantly decreased compared with that of the WKY rats, indicating the impairment of a short-term memory including reduction in attention. Also, an increase in the total number of arm entries, i.e., hyperactivity was observed in SHRSP/Ezo rats. The intraperitoneal administration of methylphenidate (0.01 to 1 mg/kg) dose-dependently improved the reduction in spontaneous alternation behavior rate in SHRSP/Ezo rats. While 1 mg/kg of methylphenidate improved the reduction in spontaneous alternation behavior rate in SHRSP/Ezo rats, a significant exaltation in the increase in the total number of arm entries was observed. Methylphenidate at 0.01 and 0.1 mg/kg had no influence on the increase in the total number of arm entries in SHRSP/Ezo rats.

(31) From the above results, SHRSP/Ezo rats, exhibiting ADHD-like symptoms such as hyperactivity, impulsivity, and inattention, was confirmed to have the face validity as an ADHD model. SHRSP/Ezo rats had also satisfied the prediction validity because methylphenidate was effective for such ADHD-like symptoms. As the dose of methylphenidate used as the comparative drug in the following evaluation of the effects of the compound for use in the invention, 1 mg/kg was determined with which an improvement in inattentive behavior was observed in the Y-maze test and the risk of worsening the hyperactivity was detectable.

(32) 2) Evaluation of Effects of Compound for Use in the Invention on Hyperactivity, Impulsivity, and Inattentive Behavior in SHRSP/Ezo Rats

(33) 2-1) Y-Maze Test

(34) As a result of the evaluation of the inattentive behavior in the Y-maze test, methylphenidate (1 mg/kg) recovered the reduction in spontaneous alternation behavior rate observed in SHRSP/Ezo rats without increasing the total number of arm entries. The subcutaneous administration of the compound for use in the invention (0.03 to 0.3 mg/kg) significantly improved the impaired alternation behavior in SHRSP/Ezo rats at 0.1 to 0.3 mg/kg, but no improvement action was observed at a dose of 0.03 mg/kg. Also, the compound for use in the invention at 0.03 to 0.3 mg/kg significantly decreased the total number of arm entries, compared with the first trial (Y1) (FIG. 1).

(35) 2-2) Open Field Test

(36) The hyperactivity of SHRSP/Ezo rats during the exploration phase (0 to 15 minutes) and the habituated phase (15 to 60 minutes) was worsened with methylphenidate (1 mg/kg) as the comparative drug. The subcutaneous administration of BPAP (0.01 to 0.3 mg/kg) significantly inhibited the increase in behavior at the habituated phase was without affecting the locomotor activity at the exploration phase with a dose of 0.01 to 0.1 mg/kg. BPAP at 0.3 mg/kg, however, had no action against the locomotor activity at the exploration and the habituated phase (FIG. 2).

(37) Since the spent time in the inner zones (nine compartments in the center) (inner zone spent time) in the open field test is used for the evaluation of the anxiety level, the spent times per time (sec/15 min) and per behavior (sec/count) corrected with the locomotor activity (total crossings) were analyzed as the secondary evaluation in the open field test (FIG. 3). Since animals normally exhibit, from anxiety, a nature of walking in a peripheral zone keeping a touch with a sidewall of the device (thigmotaxis), they little exhibit exploration behaviors into the inner zone. SHRSP/Ezo rats show an increase in spent time in the inner zone at the habituated phase during which hyperactivity was observed, indicating a reduction in anxiety level at the habituated phase. Methylphenidate (1 mg/kg) significantly increased the spent time in the inner zone at the exploration phase, and had no effect on the reduction in anxiety level at the habituated phase. BPAP (0.01 to 0.1 mg/kg) significantly reduced the inner zone spent time at the habituated phase, suggesting the possibility of amelioration of reduced level of anxiety. However, 0.3 mg/kg of BPAP had no effect on the reduction in anxiety level at habituated phase.

(38) 2-3) Elevated-Plus Maze Test

(39) In the evaluation of the impulsivity based on an anxiety-related behavior in the elevated-plus maze test, methylphenidate (1 mg/kg) significant worsened the increase in the total number of arm entries, i.e., exacerbation of the hyperactivity in SHRSP/Ezo rats. It did not improve the increase in the rate of open arm entries and the extension of the spent time on the open arms. The compound for use in the invention (0.01 to 0.3 mg/kg) had no effect on the extension of the spent time on the open arms, but it had a tendency to reduce the rate of open arm entries with a dose of 0.1 mg/kg (P=0.08). BPAP at 0.1 mg/kg significantly reduced the spent time on the open arms per total number of arm entries performed as the secondary analysis (FIG. 4).

INDUSTRIAL APPLICABILITY

(40) From the above test results, the possibility is shown that the prophylactic or therapeutic agent for ADHD according to the invention may exert an effect on impulsivity more than methylphenidate can do, and it is expected that the therapeutic effect may be exerted even on a methylphenidate-ineffective case. Also, it has become evident that the prophylactic or therapeutic agent for ADHD according to the invention exhibits an inhibition action against a methamphetamine-seeking behavior in rats (due to drug-associated cues and methamphetamine-priming) and an effective dose of the compound for use in the invention did not induce the methamphetamine-seeking behavior. As for the dependence liability of the prophylactic or therapeutic agent for ADHD according to the invention, the possibility of not creating strong dependence liability with at least a therapeutic dose has been shown. Also, while it takes time for atomoxetine to produce a stable drug efficacy, the prophylactic or therapeutic agent for ADHD according to the invention, which has the central stimulation action, is a promising drug of a type producing the efficacy as rapidly as or more rapidly than methylphenidate.

(41) From the above findings, the prophylactic or therapeutic agent for ADHD according to the invention has an efficacy spectrum different from the existing ADHD therapeutic drugs such as methylphenidate and atomoxetine, and is expected to expand the options of the drug therapy for ADHD by being used alone or in combination with other ADHD therapeutic drugs.