A long-term study of acotiamide in patients with functional dyspepsia: results from an open-label phase III trial in Japan on efficacy, safety and pattern of administration.

BACKGROUND: This long-term 48-week study of acotiamide was carried out to investigate the efficacy, safety and administration pattern in patients with functional dyspepsia (FD). METHODS: This was a multicenter, open-label, single-arm, long-term phase III study in which patients with FD were given acotiamide, 100 mg t.i.d., for 48 weeks. The two major efficacy endpoints were global overall treatment efficacy (OTE) and the elimination rate of three cardinal symptoms (i.e. postprandial fullness, early satiation and upper abdominal bloating), which were evaluated weekly and daily by the patients, respectively. The long-term administration patterns were investigated by following the patients based on cessation and readministration criteria. RESULTS: Efficacy was analyzed in 405 patients. The OTE improvement rate was 26.1% at week 1 and increased with time. It was 60.6% at week 8 and subsequently maintained. Similarly, the symptom elimination rate increased up to week 8. Many patients who met the cessation criterion achieved remission of FD symptoms after experiencing dose interruption and readministration. The incidence rate of adverse drug reactions was 11.5% and most of the adverse drug reactions were mild in severity except increased ALT in 1 patient. CONCLUSION: FD symptoms were controlled by intermittent administration of acotiamide even in patients with relapsing FD.

Intrapleural hypotonic cisplatin treatment for malignant pleural effusion in 80 patients with non-small-cell lung cancer: a multi-institutional phase II trial.

To assess the effect and toxicity of hypotonic cisplatin treatment (HPT) consisting of the intrapleural administration of cisplatin in distilled water for malignant pleural effusion in patients with non-small-cell lung cancer (NSCLC). Non-small-cell lung cancer patients with cytologically proven and previously untreated malignant pleural effusion were enrolled into this study. Firstly, the lung was fully re-expanded by a tube thoracostomy, and then 25 mg cisplatin in 500 ml of distilled water was instilled through a chest tube and then the tube was clamped. After 1 h, the tube was declamped and allowed to drain. The chest tube was removed when the pleural effusion volume decreased to 200 ml or less per day. A complete response (CR) was considered to occur when the pleural effusion disappeared. A partial response (PR) was determined to occur when the volume of pleural effusion remained under (1/4) of hemithorax. The response at 4 weeks was evaluated by an extramural review. Out of 84 patients enrolled from February 1998 to August 2002, 80 patients were eligible and analysed in the present study. The toxicity of HPT was acceptable. Neither a haematological toxicity of any grade nor grade 4 nonhaematological toxicity was observed. Grade 3 nonhaematological toxicities were observed, including nausea (4%), vomiting (3%), pyothorax (1%) and dyspnoea (1%). The median time of drainage from HTP was 4 days. Twenty-seven (34%) and 39 (49%) patients achieved CR and PR, respectively, for an overall response rate of 83% (95% confidence interval, 74-91%). The median duration of the response was 206 days. The median survival time of all patients was 239 days. Hypotonic cisplatin treatment for malignant pleural effusion of NSCLC is therefore considered to be feasible and effective. A phase III study of HPT is thus warranted.

Efficacy of sildenafil for Japanese patients with audio-visual sexual stimulation (AVSS) test by the RigiScan Plus.

Sildenafil is most effective in men with mild-to-moderate ED, but not severe ED in Japan. In order to evaluate the efficacy of sildenafil, we conducted the present study using the AVSS test by the RigiScan Plus. The subjects were 56 patients (age: 34-82 years, mean: 60.5 years) with ED. The IIEF5 questionnaire and the AVSS test were conducted before and after administration of sildenafil. The penile rigidity could not be measured in 19 patients. Of these 19, sildenafil was effective in 7 and not effective in 12. The 7 cases in whom sildenafil was effective were all false-negatives. The sensitivity of sildenafil was 84%, and its specificity was 100%. This study suggests that the AVSS test by RigiScan Plus can objectively evaluate the efficacy of sildenafil, and shows potential for predicting that efficacy.

Do motorcyclists have erectile dysfunction? A preliminary study.

The aim of the present study was to evaluate the relationship between motorcycling and erectile dysfunction (ED). We investigated the relationship between motorcycling and erectile function using the 5-items version of the International Index of Erectile Function (IIEF5) in 234 motorcyclists (response rate 75%) and 752 healthy controls (response rate 66%). In all, 161 (69%) of 234 motorcyclists were diagnosed as ED based on IIEF5. The prevalence of ED in the motorcycle group increased by age as: 58, 63, 76 and 93%, for motorcyclists in 20-29, 30-39, 40-49 and 50-59 years, respectively. There was a significant difference in the prevalence of ED between the motorcycle group and the control group in all age groups. On stepwise logistic regression analysis, motorcycling was the strongest risk factor for ED. Although the severity of ED in motorcyclists was not so severe, motorcycling may be one of risk factors for ED.

Erythrocyte aldose reductase correlates with erectile dysfunction in diabetic patients.

Erectile dysfunction (ED) is a common complication of diabetes mellitus. Erythrocyte aldose reductase (AR) has been implicated in a variety of diabetic complications. The subjects were 62 diabetic patients, of whom 25 were treated with hemodialysis (chronic renal failure CRF group) and the remaining 37 did not have chronic renal failure (DM group). The controls were 20 healthy volunteers age-matched to the patients. The level of AR was measured by the quantitative determination kit for AR in all patients and controls. In this study, ED was diagnosed by 5-item version of the International Index of Erectile Function (IIEF-5). The average level of AR in the CRF group was significantly higher than that in the DM group and controls (P<0.001). The average level of AR in the DM group without ED was significantly lower than that in the DM group with ED and controls (P<0.005). These results suggest that the level of AR may be a useful modality for prediction of ED in diabetic patients.

Significant decrease of the International Index of Erectile Function in male renal failure patients treated with hemodialysis.

In order to evaluate the erectile function in male renal failure patients treated with hemodialysis (HD), we investigated the International Index of Erectile Function (IIEF) in patients and healthy controls. The subjects were 174 male patients treated with HD, of whom 43 had diabetes mellitus (DM) and the remaining 131 patients did not have DM. The controls were 1133 healthy males. We evaluated the prevalence of erectile dysfunction (ED) using the erectile function (EF) score, which is one of the five domains of the IIEF, in each age group (upto 39 y old, 40-49 y old, 50-59 y old, 60-69 y old). The severity of ED was classified into five categories using EF in each age group. The univariate logistic regression analysis and multiple variate analysis of IIEF in HD patients were performed. The prevalence of ED in HD patients was significantly higher than that in the controls in each age group. The severity of ED in HD patients was also significantly higher than that in the controls in each age group. In the logistic regression analysis and multiple variate analysis of IIEF in HD patients, DM and age were significant risk factors on sexual dysfunction. ED was more prevalent in male renal failure patients treated with HD than in the controls. In the patient group, ED was more prevalent in older DM patients.

Spatial organization of EEG activity from alertness to sleep stage 2 in old and younger subjects.

In order to elucidate brain mechanisms that contribute to the increased tendency for vigilance dysregulation in the elderly, we examined the spatial organization of brain electric activity [electroencephalogram (EEG)] during decreasing vigilance from alertness to onset of sleep stage 2, comparing 7 old and 10 younger, healthy subjects (60-79 and 18-41 years old, respectively). Two features were analyzed: (1) change of location of the brain electric source gravity centers of the EEG frequency bands, and (2) magnitude of fluctuation of these locations over time. Multichannel EEG was analyzed into source gravity center localizations for seven EEG frequency bands, using fast Fourier transform (FFT) Dipole Approximation (first principal component-single source modeling in the frequency domain). Multivariate analysis of covariance (MANCOVA) showed: source localizations were more anterior in old than younger subjects for beta-1 and more superior for all three beta bands; from alertness to sleep, delta and theta EEG sources (inhibitory activity) changed to more posterior and superior areas, and alpha-1 and -2 (routine activity) and beta-1 and -2 sources (excitatory activity) towards anterior and superior areas. Fluctuations of the source locations of delta and beta-2 were larger on the superior--inferior axis, and of beta-2 smaller on the left-right axis in the old than younger subjects. The results suggest functional specifications (inhibitory, routine, excitatory) of cortical positron emission tomography (PET) changes reported in sleep. In sum, aging exhibits changes in spatial organization of EEG-generating neuronal assemblies; during the transition wakefulness-to-sleep, aging affects the spatial-temporal dynamics of this organization. The latter is suggested to contribute to the increased risk for consciousness disturbances in the elderly.

Possible use of ultrasound estimated bladder weight in evaluating vesicoureteral reflux in children.

The present study was designed to reveal the possible use of ultrasound estimated bladder weight (UEBW) in evaluating vesicoureteral reflux (VUR) in children in terms of possible implication of bladder hypertrophy in VUR. In 27 children with VUR, UEBW was measured by transabdominal ultrasound. The UEBW in an individual patient was evaluated quantitatively using the percent deviation from age matched UEBW. There was a significant difference noted in the percent deviation from age-matched UEBW between patients (n = 17) with primary VUR and those (n = 10) with secondary VUR (p <.05). When analyzed together in 27 patients, a significant positive correlation (p <.05) was recognized between the percent deviation from age-matched UEBW and VUR grade. This was also the case in ten patients with secondary VUR (p <.01), but not for 17 patients with primary VUR. The measurement of UEBW might be of clinical use in evaluating the pathogenesis as well as the severity of VUR in children.

Nicotine, alcohol, methamphetamine, and inhalant dependence: a comparison of clinical features with the use of a new clinical evaluation form.

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol, methamphetamine, and inhalant dependence. The clinical evaluation form consisted of six scoring items: subjective effects, tolerance, liking (of drug), social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine (n = 25), alcohol (n = 36), methamphetamine (n = 11), and inhalants (n = 6). All subjects met the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnostic criteria for drug dependence, as defined by the Work Group for the chapter "Substance-Related Disorders": M. A. Schuckit, J. E. Helzer, L. B. Cottler, T. Crowley, P. E. Nathan, & G. E. Woody. Nicotine produced subjective effects, tolerance, liking, and psychic withdrawal symptoms, all of which were mild in degree. However, nicotine did not produce social disturbance, physical withdrawal symptoms, or acute psychic or acute physical disorders. With alcohol, acute psychic and acute physical disorders were prominent, and alcohol also produced a moderate degree of influence on various other items that were evaluated. Methamphetamine produced the most serious acute psychic and acute physical disorders with intensive subjective effects. Inhalants were characterized by an intensive degree of acute psychic disorders and subjective effects with mild withdrawal syndrome. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

The effects of flumazenil on sleepiness, task performance and nocturnal sleep after anesthesia with midazolam.

The purpose of the present study was to clarify the changes in psychophysiological functions after anesthesia with midazolam (intravenous (i.v.) benzodiazepine anesthetic) and to examine the ability of flumazenil (benzodiazepine antagonist) to prevent the adverse effects of anesthesia with midazolam. Clinical dose of midazolam (0.1 mg/kg i.v.) was administered to seven healthy volunteers and either flumazenil (0.3 mg i.v.) or saline was injected at the end of the anesthesia. After anesthesia with midazolam, subjective sleepiness and euphoria increased significantly, but these changes were not observed when flumazenil was administered. In addition, sleep latency was prolonged and sleep efficiency decreased significantly after midazolam anesthesia with and without flumazenil. Slow wave sleep decreased significantly only by co-administration of flumazenil.

DNA methyltransferase expression and DNA methylation of CPG islands and peri-centromeric satellite regions in human colorectal and stomach cancers.

We evaluated the significance of aberrant DNA methyltransferase expression in human carcinogenesis by examining 32 colorectal and 34 stomach cancers. Levels of mRNAs encoding DNA methyltransferases were measured by reverse transcription, followed by real-time quantitative detection of PCR products. The DNA methylation state of CpG islands and peri-centromeric satellite regions was examined by bisulfite modification and Southern blotting, respectively. The average level of mRNA for DNMT1 and DNMT3b in colorectal and stomach cancers was significantly higher than in corresponding non-cancerous mucosae, whereas the average level of mRNA for DNMT2 was significantly lower in colorectal and stomach cancers than in non-cancerous tissue. Over-expression of DNMT3b in stomach cancer was significantly higher in cases with lymph node metastasis than in cases without. DNA hypermethylation on the p16, human Mut L homologue-1 and thrombospondin-1 genes and the methylated in tumor (MINT) 1, 2, 12, 25 and 31 clones was found in 23%, 27%, 9%, 23%, 20%, 23%, 20% and 10% of the colon cancers and in 9%, 19%, 30%, 25%, 34%, 19%, 81% and 3% of the stomach cancers, respectively. Criteria for identification of the CpG island methylator phenotype (CIMP) were met in 23% of colorectal cancers and 31% of stomach cancers. DNA hypomethylation on satellites 2 and 3 was detected in 0% and 8% of colorectal and stomach cancers, respectively. Over-expression of DNMT1 mRNA was significantly associated with CIMP, whereas the level of DNMT3b mRNA was not associated with CIMP or DNA hypomethylation of peri-centromeric satellite regions. These data suggest that both over-expression of the maintenance DNA methyltransferase DNMT1 and over-expression of a newly identified de novo DNA methyltransferase, DNMT3b, are involved in human carcinogenesis, probably at different stages and through different mechanisms.

MRNA expression of genes altered by 5-azacytidine treatment in cancer cell lines is associated with clinicopathological parameters of human cancers.

OBJECTIVE: We attempted to identify tumor-related genes whose expression is affected by DNA methylation and that participate in the determination of the biological characteristics of human cancers. METHODS AND MATERIALS: We used the differential display method in ten 5-azacytidine-treated human cancer cell lines. Time-dependent induction of mRNA expression of Wip1, TROP2, B4-2 protein, BRCA-2 region transcription unit CG005, cofilin, ROCK, CD44. and interferon-inducible protein 6-16 was observed during 5-azacytidine treatment. We then evaluated the mRNA expression of these genes in 26 stomach and 32 colorectal cancers and 44 hepatocellular carcinomas (HCCs) and in the corresponding non-cancerous tissues. RESULTS: Significantly reduced mRNA expression of Wip1, B4-2, and cofilin in stomach cancers, of Wip1, B4-2, BRCA-2 region transcription unit CG005, cofilin, and ROCK in colorectal cancers, and of TROP2, B4-2, and BRCA-2 region transcription unit CG005 in HCCs, was observed in comparison with the corresponding non-cancerous tissues, whereas overexpression of TROP2 was detected in colorectal cancers. Reduced expression of Wip1 and BRCA-2 region transcription unit CG005 was significantly correlated with poorer differentiation of HCCs, and mRNA expression of these genes was significantly reduced in HCCs associated with portal vein involvement compared with HCCs without such involvement. Expression of TROP2 mRNA was significantly higher in chronically diseased liver from HCC patients compared with histologically normal liver, but was reduced in progressed HCCs. Reduced expression of B4-2 protein was observed in association with hepatitis B virus infection of HCC patients. CONCLUSIONS: These data suggest that DNA methylation may play a role in human multistage carcinogenesis through direct or indirect regulation of multiple tumor-related genes.

Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis.

The aim of this study was to examine the significance of aberrant DNA methylation, the participation of which in genetic instability is controversial, in hepatocarcinogenesis. The DNA methylation status of the region around the promoter of the E-cadherin tumor suppressor gene, which is located on 16q22.1, and the allelic status at the D16S421 locus, which is adjacent to the E-cadherin locus, were examined using microdissected liver specimens from 38 hepatocellular carcinoma (HCC) patients. Almost all of the non-cancerous liver tissues showed histological findings compatible with chronic hepatitis and cirrhosis, which are considered to be precancerous conditions. DNA hypermethylation was detected in 61% of the non-cancerous liver tissues. The incidence of DNA hypermethylation in the non-cancerous liver tissues of patients with HCCs also showing DNA hypermethylation (72%) was significantly higher than that of patients without DNA hypermethylation in their HCCs (53%, P<0.05). Loss of heterozygosity (LOH) at the D16S421 locus was detected in 35% of the non-cancerous liver tissues. The incidence of LOH in the non-cancerous liver tissues of patients with HCCs also showing LOH was 78%, whereas LOH was not detected in non-cancerous liver tissues of patients without LOH in their HCCs. Fifty-two percent of the non-cancerous liver tissues showed both or neither of DNA hypermethylation and LOH; the incidence of DNA hypermethylation alone in noncancerous liver tissue was 41%. The incidence of LOH alone in non-cancerous liver tissue (7%) was significantly lower compared to those of the former two cases (P<0.0001). These data suggest that aberrant DNA methylation participates in the precancerous stage of hepatocarcinogenesis by preceding, or causing, LOH.

Changes in subjective sleepiness, subjective fatigue and nocturnal sleep after anaesthesia with propofol.

The purpose of this study was to clarify the changes in psycho-physiological functions after anaesthesia with propofol (PF). The subjects were seven healthy male volunteers and the duration of the anaesthesia was 1 h (14:00-15:00 h). The plasma concentration of PF immediately decreased after the anaesthesia. The subjective sleepiness and VAS (visual liner analogue scale) scores (i.e. effort to do something) increased significantly at 20 min after the anaesthesia. However, these changes were improved at 80 min after the anaesthesia. The sleep latency at the nocturnal sleep 8 h after the anaesthesia was prolonged significantly, but the other parameters including the distributions of stage 3 + 4 and the rapid eye movement 'REM' stage were not changed.

Sleep architectures of obstructive sleep apnea syndrome in the young child.

The sleep architectures of obstructive sleep apnea syndrome (OSAS) in the young child (child-OSAS, n = 17; mean age: 5.9+/-2.7 years; male:female 14:3) were compared with that of OSAS in the adult (n = 19; mean age: 44.7+/-10.7 years; male:female 18:1) and that of primary snoring in the child (n = 5; mean age: 7.0+/-2.4 years; male:female 5:0). Child-OSAS and OSAS in the adult had the same severity in oxygen desaturation. Child-OSAS showed lower Apnea-Hypopnea Index compared with OSAS in the adult. Sleep continuity in child-OSAS was not impaired compared with OSAS in the adult. Sleep fragmentation in child-OSAS was not so remarkable. The quantity of slow wave sleep in child-OSAS was similar to that of primary snoring in the child. Both profiles of sleep architectures showed nearly the same pattern.

Effect of 3 mg melatonin on jet lag syndrome in an 8-h eastward flight.

In order to assess the effect of melatonin on jet lag a field study was undertaken. The process of re-entrainment of circadian melatonin rhythm was investigated in six subjects. Except during 24-h blood sampling, the subjects were exposed to natural zeitgeber (time giver) outdoors and given 3 mg melatonin at 23:00 h. The subjects were exposed to bright sunlight from 3000 to 12000 lx. All of them showed orthodromic re-entrainment with taking melatonin, while two out of the six did not show orthodromic re-entrainment without taking melatonin. Melatonin accelerated the rate of the re-entrainment of the circadian melatonin rhythm. Melatonin was useful to jet travel from Tokyo to Los Angeles.