Taro Muramatsu

Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study

BACKGROUND Pruritus in haemodialysis patients is an intractable disease and substantially impairs their quality of life. Based on the results of our earlier clinical study, we hypothesized that the micro-(mu) opioid system is itch-inducible, whereas the kappa (kappa) system is itch-suppressive. METHODS The efficacy and safety of nalfurafine hydrochloride (a novel kappa-receptor agonist) were prospectively investigated by randomly (1:1:1) administering 5 or 2.5 microg of the drug or a placebo orally for 14 days using a double-blind design in 337 haemodialysis patients with itch that was resistant to currently available treatments, such as antihistamines. RESULTS The mean decrease in the visual analogue scale (VAS) from baseline, the studys primary endpoint, was significantly larger in the 5-microg nalfurafine hydrochloride group (n = 114) than in the placebo group (n = 111, P = 0.0002, one-sided test at 2.5% significance level). The decrease in the VAS in the 2.5-microg group (n = 112) was also significantly larger than that in the placebo group (P = 0.0001). The incidence of adverse drug reactions (ADRs) was 35.1% in the 5-microg group, 25.0% in the 2.5-microg group and 16.2% in the placebo group. Moderate to severe ADRs were observed in 10 of the 226 patients. The most common ADR was insomnia (sleep disturbance), seen in 24 of the 226 nalfurafine patients. CONCLUSIONS This Phase III, randomized, double-blind, placebo-controlled, parallel-group, prospective study based on VAS evaluations clearly showed that orally taken nalfurafine hydrochloride effectively reduced itches that were otherwise refractory to currently available treatments in maintenance haemodialysis patients, with few significant ADRs. This novel drug was officially approved for clinical use in January 2009 by the Ministry of Health, Labour and Welfare of Japan.

Association between dopamine D4 receptor (D4DR) Exon III polymorphism and novelty seeking in Japanese subjects

This study was designed to assess the association between novelty seeking and D4DR gene polymorphism in the Japanese population. The 48 bp repeat polymorphism in the third exon of the dopamine D4 receptor gene of 153 normal female students was correlated with personality feature results from the Japanese version of Cloningers Temperament and Character Inventory. The Novelty Seeking subscale of Exploratory Excitability had a significant association with long alleles of the polymorphic exon III repeat sequence of D4DR. Our results suggest that there is an association between long alleles of the polymorphic exon III repeat sequence of D4DR and the personality traits of the Novelty Seeking subscale of Exploratory Excitability, regardless of racial differences in the frequencies of D4DR exon III repeat polymorphism.

Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders

Disturbances in dopaminergic systems have been implicated in the etiology of mood disorders. Although genetic factors also play an important role, no major gene has been identified. We conducted an association study using the dopamine D2, D3 and D4 receptor, and transporter gene polymorphisms, comparing 101 mood-disorder patients (52 bipolar and 49 unipolar) and 100 controls. Our results suggest that there is a significant association between the dopamine D4 receptor gene and mood disorders, especially major depression, but no association between the other polymorphisms and mood disorders. Further investigations are needed to clarify the clinical significance of this association in the pathophysiology of mood disorders.

Gaze but not arrows: A dissociative impairment after right superior temporal gyrus damage

Superior temporal sulcus (STS) activation has consistently been demonstrated in the normal brain when viewing eyes, and thus this area is implicated as a gaze processing region in humans. In a recent report, we have presented a case, M.J., with a well-circumscribed lesion to the right superior temporal gyrus (STG), who demonstrated impaired discrimination of gaze direction. In the aim to make distinct whether this impairment is unique to gaze, we have applied a spatial cueing paradigm established by Kingstone and colleagues. In our experiment, pictorial gaze and symmetrical arrows were centrally presented as non-predictive, spatial cues in detecting peripheral targets. Fifteen normal subjects and M.J. participated in the experiment. In concordance with previous reports, controls demonstrated a significant facilitation of reaction times in detecting targets cued by congruent gaze/arrows, compared with incongruent cues. In striking contrast, M.J. showed no such congruency advantage for gaze, in the face of a normal congruency advantage for arrows. We have demonstrated that a circumscribed lesion to the right STG impairs the ability to utilize biological directional information such as gaze, but leaves the non-biological counterpart (arrows) intact. This dissociation implies that indeed, the STS specializes in processing gaze.

Association between alcoholism and the dopamine D4 receptor gene.

A point mutation in the aldehyde dehydrogenase 2 gene (ALDH2(2) allele) is considered to be a genetic deterrent for alcoholism; however, 80 of 655 Japanese alcoholics had the mutant allele. Genotype factors that might increase susceptibility by overriding the deterrent showed a higher frequency of a five repeat allele of the dopamine D4 receptor 48 bp repeat polymorphism in alcoholics with ALDH2(2) than in 100 other alcoholics and 144 controls. Alcoholics with the five repeat allele also abused other drugs more often. These data suggest the involvement of the dopamine system in the development of alcoholism and other addictive behaviour.

Cancer screening of upper aerodigestive tract in Japanese alcoholics with reference to drinking and smoking habits and aldehyde dehydrogenase-2 genotype

In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer‐detection rates, drinking and smoking habits, and aldehyde dehydrogenase‐2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal‐cancer patients were multiple‐cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack‐years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2*1/2*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple‐cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These results show that the 3 risk factors are important for the development of upper‐aerodigestive‐tract cancer in Japanese alcoholics. For these high‐risk drinkers, regimented screening appears to be indicated.

Efficacy and Safety of a Novel ĸ-Agonist for Managing Intractable Pruritus in Dialysis Patients

Background: Our previous placebo-controlled, prospective, double-blind study demonstrated that a new opioid ĸ-receptor agonist, nalfurafine hydrochloride, effectively reduced treatment-resistant pruritus in 337 hemodialysis patients. Thus, we designed this study to evaluate prospectively the efficacy, safety, addiction liability, and pharmacokinetics of nalfurafine given orally for 1 year. Methods: This open-label study examined the effects and adverse drug reactions (ADRs) of 52-week oral administration of nalfurafine hydrochloride (5 µg/day) in 211 hemodialysis patients with a treatment-resistant itch. Results: Of 211 patients, 145 completed the study as scheduled. The mean pruritus value assessed by the visual analogue scale was 75.2 mm during the pre-observation period, which decreased significantly to 50.9 and 30.9 mm in week 2 and 52, respectively, indicating a long-lasting efficacy. ADRs occurred in 103 patients (48.8%). Frequent ADRs were insomnia (sleep disturbance, 19.4%), constipation (7.1%) and increased blood prolactin (3.3%), similar to previous reports. Regarding addiction liability, it appeared unlikely that nalfurafine hydrochloride was abused. After the start of treatment, plasma drug levels reached a steady state in week 2 with no apparent tendency of systemic accumulation. Conclusions: Nalfurafine hydrochloride, orally administered at 5 µg/day for 52 weeks to hemodialysis patients, produced a long-term suppression of pruritus without significant safety problems.

A deficit in discriminating gaze direction in a case with right superior temporal gyrus lesion

The superior temporal sulcus (STS) region is well recognized as being heavily involved in detecting and discriminating gaze. Lesions confined to this area are quite rare in humans, and so the research has mainly depended on animal studies and functional neuroimaging in normal human subjects. We report one such rare case, a 54-year-old Japanese female with a possible congenital s anomaly who, after a cerebral hemorrhage, demonstrated a lesion almost completely confined to the entire right superior temporal gyrus (STG). In the subacute phase, the patient showed evidence of left hemispatial neglect, from which she gradually recovered. In the chronic phase, she showed a puzzling difficulty in obtaining eye-contact. We have conducted, in conjunction with conventional neuropsychological evaluations, experimental assessment of her ability in gaze cognition. Her performance on neuropsychological testing demonstrated no compromise in intellect, memory, or language skills, and a close-to-full recovery from neglect. On gaze cognition experiments, she was repeatedly shown to perceive left gaze as straight, and to a lesser degree, straight gaze as right. We suggest that the function of the STG in detecting gaze, together with the directional information it receives from earlier visual areas, may be associated, when damaged, with this deficit in detecting contra-directional gaze. We have demonstrated for the first time that a single circumscribed lesion to the STG results in both gaze processing deficit and concurrent aberrant gaze behavior of the victim herself, implicating a mechanism within the STG as an interface between gaze of others and gaze of self.

The frequency of the methylenetetrahydrofolate reductase-gene mutation varies with age in the normal population.

To the Editor:Cardiovascular disease and cerebrovascular disease are second only to cancer as the leading causes of death in Japan, and their mortality rates rise with the age of the population (Health and Welfare Statistics Association 1995xHealth and Welfare Statistics Association. See all ReferencesHealth and Welfare Statistics Association 1995). In addition to environmental factors such as smoking, genetic factors are involved in determining an individuals susceptibility to vascular disease. Because low frequency of genetic risk factors for vascular disease could contribute to a populations longevity, the frequency of potentially protective genotypes may be higher in the oldest segment of the population.For the past decade, mild hyperhomocysteinemia has been recognized as a risk factor for occlusive arterial disease and thrombosis. Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the methylation of homocysteine. A homozygous mutation of the MTHFR gene (677C →T; A→V) alters a highly conserved amino acid, resulting in decreased specific MTHFR activity and elevated levels of homocysteine (Frosst et al. 1995xA candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJH et al. Nat Genet. 1995; 10: 111–113Crossref | PubMed | Scopus (4201)See all ReferencesFrosst et al. 1995). According to a recent report on patients with premature vascular disease, this mutation is associated with a threefold increase in risk for premature cardiovascular disease (Kluijtmans et al. 1996xMolecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Kluijtmans, LAJ, van den Heuvel, LPWJ, Boers, GHJ, Frosst, P, Stevens, EMB, van Oost, BA, den Heijer, M et al. Am J Hum Genet. 1996; 58: 35–41PubMedSee all ReferencesKluijtmans et al. 1996).Individuals with the homozygous 677C→T mutation have been reported to show increased thermolability of MTHFR (Frosst et al. 1995xA candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJH et al. Nat Genet. 1995; 10: 111–113Crossref | PubMed | Scopus (4201)See all ReferencesFrosst et al. 1995). One study attributed the abnormal homocysteine metabolism in 28% of the homocysteinemic patients with premature vascular disease to thermolabile MTHFR (Engbersen et al. 1995xThermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Engbersen, AMT, Franken, DG, Boers, GHJ, Stevens, EMB, Trijbels, FJM, and Blom, HJ. Am J Hum Genet. 1995; 56: 142–150PubMedSee all ReferencesEngbersen et al. 1995). Another study indicated that an association between the thermolabile MTHFR defect and coronary artery disease is independent of other known risk factors for coronary artery disease (Kang et al. 1993xThermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Kang, SS, Passen, EL, Ruggie, N, Wong, PWK, and Sora, H. Circulation. 1993; 88: 1463–1469Crossref | PubMedSee all ReferencesKang et al. 1993).These observations led us to speculate that the MTHFR mutation may be partly responsible for cardiovascular disease, thus decreasing the probability of an individuals reaching old age. To test this hypothesis, we investigated the frequency of the MTHFR mutation in 945 unrelated, healthy subjects 14–99 years old, all Japanese living in a single local area. Information about health condition (e.g., history of hypertension, hyperlipidemia, diabetes mellitus, stroke, and heart disease) was obtained by semistructured interview of 506 subjects who were >60 years old. We assessed blood pressure at rest twice during the interview.Taking account of the rising rate of mortality due to cardiovascular and cerebrovascular diseases in people >80 years old, we stratified the subjects into three age groups: younger (≤54 years; n=311), older (55–79 years; n=486), and oldest (⩾80 years; n=148, of whom 22 were ⩾90 years of age). DNA was extracted from peripheral leukocytes obtained from each subject, and MTHFR genotyping was performed as described by Frosst et al. (1995)xA candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJH et al. Nat Genet. 1995; 10: 111–113Crossref | PubMed | Scopus (4201)See all ReferencesFrosst et al. (1995).As shown in table 1table 1, the MTHFR mutation decreased as the ages of the subjects increased. The homozygous MTHFR mutation occurred in 19% of the younger group and in 14% of the older group, whereas we found the mutation in only 7% of the oldest group. The homozygous mutation occurred significantly less often in both the older and oldest groups than in the younger group, especially among males (total—df=2, χ2=10.39, P=.006; males—df=2, χ2=7.25, P=.027; females—df=2, χ2=3.59, P=.166). The MTHFR-genotype distributions for the younger and older age groups were in Hardy-Weinberg equilibrium, but the distribution for octogenarians and nonagenarians was not (i.e., there was a nonsignificant trend, χ2=4.71, P<.1). However, none of the nonagenarians carried the homozygous MTHFR mutation. This finding led us to compare the frequency of past illness and blood pressure among subjects of each age group.Table 1MTHFR Genotype in Healthy Japanese Stratified by Age Groups and GenderYounger (<55 years)Older (55–79 years)Oldest (⩾80 years)MTHFR AlleleaaMTHFR AlleleaaMTHFR Alleleaan+/++/− or −/−n+/++/− or −/−n+/++/− or −/−Malebb147.21.79227.15.8579.08.92Female164.17.83259.13.8769.07.93 Totalcc311.19.81486.14.86148.07.93aA plus sign (+) denotes the mutant allele; and a minus sign (−) denotes the wild-type allele.bχ2=7.25, P=.027, for differences among the three age groups.cχ2=10.39, P=.006, for differences among the three age groups.As shown in table 2table 2, there were no significant differences between MTHFR-genotype distribution and the frequency of any past illness (e.g., hypertension, hyperlipidemia, diabetes mellitus, stroke, and heart disease) among the older group, but among the oldest group the frequency of hypertension history was lower among subjects with the homozygous MTHFR mutation. Although this difference was statistically significant according to the χ2 test with continuity correction, this significance should be interpreted carefully because of the small number of subjects with the homozygous MTHFR mutation.Table 2Frequency of Hypertension History and Mean Blood Pressure at Rest, among MTHFR Genotypes, Stratified by Age GroupsMTHFR AlleleaaOlder Group (55–79 years)Oldest Group (⩾80 years)+/+ (n=57)+/− or −/− (n=333)+/+ (n=11)+/− or −/− (n=107)No. of individuals with hypertension: Present23 (40.4%)116 (34.8%)0bb44 (41.1%) Absent34 (59.6%)217 (65.2%)11 (100%)63 (58.9%)Mean (SD) maximum blood pressure at rest (mmHg)142.5 (35.2)145.1 (33.4)147.3 (28.0)149.9 (30.2)aA plus sign (+) denotes the mutant allele; and a minus sign (−) denotes the wild-type allele.bdf=1, χ2=5.56, P=.018, with continuity correction.Our results suggest that the homozygous MTHFR mutation is a genetic factor that prevents the attainment of old age. Moreover, it might indicate that persons who had the homozygous MTHFR mutation, especially those with high blood pressure, could not attain old age. However, the finding, among both old age groups, that there were no blood-pressure differences in subjects with the homozygous MTHFR mutation versus those with other genotypes suggests that some other genetic or environmental factors influence longevity. Because folate supplementation lowers homocysteine concentrations in subjects with hyperhomocysteinemia (Boushey et al. 1995xA quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. Boushey, CJ, Beresford, SSA, Omenn, GS, and Motulsky, A. JAMA. 1995; 274: 1049–1057Crossref | PubMed | Scopus (3147)See all ReferencesBoushey et al. 1995), increased folate intake may promote the longevity of subjects with the homozygous MTHFR mutation. Further investigation, focusing on this mutation and other possible risk factors and on their interaction with other nutritional and genetic factors, as well as the determination of the frequency of the MTHFR mutation in centenarians, is warranted to clarify the association between the MTHFR mutation and longevity.

Polymorphisms of dopamine receptor and transporter genes and Parkinson's disease

SummaryDisturbances of the dopamine system are involved in the pathogenesis of idiopathic Parkinsons disease (PD). Although genetic factors may play a role in the etiology of PD, there is little direct evidence implicating a specific gene. We conducted a study to test the hypothesis that allelic variations of the dopamine receptors (D2, D3, D4) and the dopamine transporter (DAT) contribute to the susceptibility to PD. Association analyses of 70 Japanese PD patients and the same number of age-matched controls did not reveal any association between alleles of the D2, D3 or D4 receptor genes or the DAT gene and PD. Thus, our results suggest that factor(s) other than allelic variations of these key proteins in the dopamine system contribute to the susceptibility to PD.