Seizaburo Kashiwagi

Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia: Fukuoka atherosclerosis trial (FAST)

OBJECTIVES This study investigated the effect of reducing serum lipids on carotid artery intima-media thickness (IMT) in asymptomatic patients with hypercholesterolemia from Fukuoka, Japan. BACKGROUND Carotid atherosclerosis is a strong, independent predictor of morbidity and mortality in patients with coronary heart disease (CHD). METHODS A total of 246 asymptomatic hypercholesterolemic patients (mean age 66 years) were randomized to receive either probucol (500 mg/day, n = 82) or pravastatin (10 mg/day, n = 83) or to enter a control group (diet alone, n = 81); they were followed for two years. The change in IMT in the common carotid artery was the primary end point measure, and the incidence of major cardiovascular events was the secondary measure. RESULTS Over the two-year period, serum low-density lipoprotein (LDL) cholesterol was significantly reduced in the pravastatin group (36%), the probucol group (29%) and the control group (12%) (p < 0.0001, p < 0.0001 and p < 0.05, respectively). After two years, the probucol and pravastatin groups showed a significant reduction in IMT (-13.9% and -13.9% and p < 0.01 and p < 0.01, respectively), but there was significant IMT thickening (23.2%; p < 0.05) in the control group. Probucol reduced the rate of IMT increase, independently of its reduction of LDL or high-density lipoprotein cholesterol. Moreover, there was a significantly lower incidence of cardiac events in the probucol group (2.4%) than in the control group (13.6%) (p = 0.0136). CONCLUSIONS Probucol reduced cholesterol levels and stabilized plaque, leading to a lower incidence of cardiac events in these hypercholesterolemic patients.

Short-term interferon-alfa therapy for acute hepatitis C : a randomized controlled trial

Acute hepatitis C often progresses to chronic infection. We undertook a randomized controlled trial to determine whether short‐term therapy with interferon (IFN) during acute hepatitis C is effective in preventing the development of chronic hepatitis. Thirty patients with acute hepatitis C were randomized into 1 of 2 treatment groups. IFN therapy was initiated 8 weeks after the onset of acute hepatitis in the early‐intervention group and after 1 year of observation in the late‐intervention group. Short‐term therapy consisted of natural IFN‐alfa (6 million units) administered on consecutive days for a period of 4 weeks. Any signs of recrudescence of disease were immediately followed by interval IFN therapy (3 times weekly for 20 weeks). In the early‐intervention group, short‐term therapy was associated with a sustained virological response in 13 of 15 patients (87%). Follow‐up treatment was associated with a sustained virological response in both of the remaining 2 patients (100%). The sustained virological response rate was significantly higher in the early‐intervention group (87%, 13 of 15 patients after short‐term therapy alone, and 100%, 15 of 15 patients after short‐term with or without follow‐up therapy) than in the late‐intervention group (40%, 6 of 15 patients after short‐term therapy alone, and 53%, 8 of 15 patients after short‐term therapy with or without follow‐up therapy, P = .021 and P = .006, respectively). In conclusion, short‐term (4 weeks) IFN treatment of patients with acute hepatitis C may be associated with satisfactory results, if initiated at an early stage of the disease. (HEPATOLOGY 2004;39:1213–1219.)

A Comparison of the Effectiveness of Oseltamivir for the Treatment of Influenza A and Influenza B: A Japanese Multicenter Study of the 2003–2004 and 2004–2005 Influenza Seasons

BACKGROUND To compare the effectiveness of oseltamivir for treatment of influenza A and influenza B, we conducted a prospective, multicenter study of the 2003-2004 and 2004-2005 influenza seasons. The study included 3351 patients in whom influenza had been diagnosed by use of an antigen detection test kit. METHODS Oseltamivir was administered to 1818 patients with influenza A and 1485 patients with influenza B. No anti-influenza drugs were administered to 21 patients with influenza A or to 27 patients with influenza B. Patients receiving oseltamivir therapy were divided into 4 groups according to the time between the onset of fever (temperature, > or = 37.5 degrees C) and administration of the first dose of oseltamivir (0-12 h, 13-24 h, 25-36 h, and 37-48 h). The patients were also divided into 4 subgroups on the basis of age (0-6 years, 7-15 years, 16-64 years, and >64 years). Virus isolation was performed after completion of oseltamivir therapy for 44 patients with influenza A and 31 patients with influenza B. RESULTS The duration of fever was significantly shorter for patients with influenza A and B who were treated with oseltamivir than for patients who were not treated with an anti-influenza drug (P<.001 for both). The time until the patient became afebrile after the initial administration of oseltamivir and the duration of fever were significantly longer for patients with influenza B than for patients with influenza A for the 0-12 h, 13-24 h, 25-36 h, and 37-48 h groups (P<.001) and for all age groups (P<.001). After 4-6 days of oseltamivir therapy, the influenza B virus reisolation rate (51.6%) was significantly higher than the influenza A virus reisolation rate (15.9%) (P<.001). CONCLUSION Oseltamivir is less effective for influenza B than for influenza A with regard to duration of fever and virus persistence, irrespective of patient age or the timing of administration of the first dose.

Factors Influencing the Effectiveness of Oseltamivir and Amantadine for the Treatment of Influenza: A Multicenter Study from Japan of the 2002—2003 Influenza Season

BACKGROUND To evaluate the effectiveness of oseltamivir and amantadine for the treatment of influenza with respect to various clinical factors, a prospective multicenter study of the influenza season of 2002-2003 was done with 2163 patients whose condition was diagnosed by an antigen-detection test kit. METHODS Oseltamivir was administered to 803 patients with influenza A (A+Os group) and 684 patients with influenza B (B+Os group). Amantadine was administered to 676 patients with influenza A (A+Am group). RESULTS For each group, the duration of fever (i.e., body temperature, > or = 37.5 degrees C) was significantly shorter in patients who received the drug within 12 h after the onset of symptoms than in patients who received the drug > 12 h after the onset. For all 3 groups, the duration of fever was shorter in patients with a highest temperature < 39 degrees C than in patients with temperatures > or = 39 degrees C. The duration of fever was significantly longer for the B+Os group than for the A+Os group. Multiple regression analysis found that the type of influenza, the highest body temperature, and the time between the onset of symptoms and the start of treatment are independent factor that influence the duration of fever. CONCLUSIONS Early administration increases the benefit of anti-influenza drugs--not only the benefit of oseltamivir treatment for influenza A, but also the benefit of amantadine treatment for influenza A and oseltamivir treatment for influenza B. Oseltamivir may be less effective as a treatment for influenza B than for influenza A. A highest body temperature of > or = 39 degrees C was an indicator of a longer duration of fever.

Factors contributing to ribavirin-induced anemia.

Background and Aim:  Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin‐induced anemia.

Clinical Effectiveness of Oseltamivir and Zanamivir for Treatment of Influenza A Virus Subtype H1N1 with the H274Y Mutation: A Japanese, Multicenter Study of the 2007–2008 and 2008–2009 Influenza Seasons

BACKGROUND Influenza A virus subtype H1N1 with the H274Y mutation emerged and spread worldwide. However, the clinical effectiveness of the neuraminidase inhibitors, oseltamivir and zanamivir, has not been adequately reevaluated. METHODS Data from 164 patients with H1N1 virus infection and 59 patients with H3N2 virus infection during the 2008-2009 influenza season and 68 patients with H1N1 virus infection during the 2007-2008 influenza season who received a neuraminidase inhibitor were analyzed. The duration of fever (body temperature 37.5 degrees C) after the first dose of oseltamivir or zanamivir and from onset of symptoms was calculated from patient reports. The influenza virus was isolated, and its subtype was determined by hemagglutinin inhibition assay and polymerase chain reaction. The H274Y neuraminidase mutation status was determined by sequencing the neuraminidase segment. RESULTS Of 68 patients with H1N1 virus infection during the 2007-2008 season, 41 were treated with oseltamivir, and 27 were treated with zanamivir. During the 2008-2009 season, 77 patients with H1N1 virus infection were treated with oseltamivir, and 87 were treated with zanamivir; 31 and 28 patients with H3N2 virus infection were treated with oseltamivir and zanamivir, respectively. All 49 analyzed H1N1 virus isolates obtained during the 2008-2009 season, but none of the isolates obtained during the 2007-2008 season, contained the H274Y mutation. The mean +/- standard deviation duration of fever after the start of oseltamivir therapy was significantly longer for patients with H1N1 virus infection (49.1+/-30.2 h) than it was for patients with H3N2 virus infection (33.7+/-20.1 h; P < .01) during the 2008-2009 season and patients with H1N1 virus infection during the 2007-2008 season (32.0+/-18.9 h; P < .001). The duration of fever was significantly longer after the first dose of oseltamivir than it was after the first dose of zanamivir for patients with H1N1 virus infection during the 2008-2009 season (P <.001). The duration of fever from onset of H1N1 virus infection was significantly longer for children 15 years of age during 2008-2009 (70.6+/-34.5 h) than it was for such children during 2007-2008 (48.4+/-21.2). CONCLUSION The effectiveness of oseltamivir, but not that of zanamivir, decreased significantly for H1N1 virus infection during the 2008-2009 season.

A Relationship between the Evolution of Hepatitis C Virus Variants, Liver Damage, and Hepatocellular Carcinoma in Patients with Hepatitis C Viremia

To clarify the mechanism of liver damage induced by hepatitis C virus (HCV) and to determine whether the damage is related to hepatocellular carcinoma (HCC), HCV RNA levels were measured serially, and HCV genome mutations were analyzed from serum of 274 Japanese patients with chronic HCV viremia during 1993-1998. All patients had alanine aminotransferase (ALT) levels measured during 1986-1998. Patients with consistently normal ALT levels had identical and highly conserved HCV core regions; however, those with consistently abnormal ALT levels had quasi species, and the population of the quasi species changed over time. HCV RNA levels did not change in the 274 patients. HCC developed in 31% of 80 patients with consistently abnormal ALT levels and in 4% of 92 patients with intermittently abnormal ALT levels but never in 102 patients with ALT levels consistently normal during 1993-1998. In patients with chronic HCV viremia, persistent liver damage plays an important role in the development of HCC.

Maintenance hemodialysis decreases serum Hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection

OBJECTIVE:Hepatitis C virus (HCV) infection is a major complication among hemodialysis patients the world over. To determine the natural course of HCV viremic levels in patients on maintenance hemodialysis, we prospectively quantified the HCV RNA levels in serial blood samples from hemodialysis patients and compared them with those in nonuremic subjects.METHODS:The population studied included 98 hemodialysis patients and 228 nonuremic subjects with chronic HCV infection. HCV RNA was detected by polymerase chain reaction (PCR) and the levels were determined by branched DNA probe assay. HCV RNA genotypes were determined by PCR using type-specific primers.RESULTS:HCV RNA levels were significantly lower in hemodialysis patients (median, 0.4 × 106 genome equivalent [Meq;[sol;ml) than in nonuremic subjects (median, 3.0 Meq/ml) (p < 0.05). HCV of genotype 1b was prevalent in the hemodialysis patients (81.6%) and nonuremic subjects (88.6%). HCV RNA levels in 20 hemodialysis patients with genotype 1b were significantly reduced after each hemodialysis procedure (p < 0.05). The 3-yr prospective observation from 1995 to 1998 showed a significant decrease of HCV RNA levels in 47 hemodialysis patients with genotype 1b (median, 1.9–0.9 Meq/ml, p < 0.05), whereas levels in 155 nonuremic subjects with genotype 1b did not decrease (median, 2.6–3.0 Meq/ml). There were no patients or nonuremic subjects with undetectable HCV RNA by a PCR assay during the observation period.CONCLUSIONS:These observations suggest that maintenance hemodialysis decreases the HCV RNA levels in hemodialysis patients with chronic HCV infection, but does not produce clearance of the viremia.

Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug-naive and HAART-treated HIV type 1-infected patients

To investigate HIV-1-related B cell disorders, the quantity of CD27 positive (CD27+) B cells and their CD38, CD95, and bcl-2 intensities were examined by flow cytometry analysis in 16 drug-naive patients, 27 highly active antiretroviral therapy (HAART)-treated patients, and 20 uninfected controls. CD27+ B cells have been recognized as memory B cells. The mean percentage of CD27+ B cells was significantly lower in drug-naive patients (11.9%) and in HAART-treated patients (16.1%) than in controls (31.4%) (p < 0.01). The intensities of CD38 and CD95 on CD27+ B cells were higher in drug-naive patients than in controls (p < 0.01 in CD95). The intensity of CD95 on CD27+ B cells in HAART-treated patients was lower than that of drug-naive patients, but significantly higher than that of controls (p < 0.01). The intensity of bcl-2 on CD27+ B cells was equivalent among the three groups. These findings suggest that disturbance of peripheral B cell composition, exemplified by CD27+ B cell reduction, exists in both drug-naive and HAART-treated HIV-1-infected patients. In addition, the augmented apoptotic state of CD27+ B cells found in HAART-treated patients with undetectable viral loads, indicated by CD95 elevation, suggests that some HIV-1-related B cell disorders last for years after effective antiviral therapy.

A prospective, Internet-based study of the effectiveness and safety of influenza vaccination in the 2001-2002 influenza season.

The effectiveness of the influenza vaccine used in the 2001-2002 influenza season in Japan was investigated in a large-scale, geographically widely distributed, Internet-based study. Data were collected from 8841 of 9902 subjects registered by 38 clinics prior to the start of influenza season. Subjects were categorized into three groups by vaccination regimen: unvaccinated, vaccinated once, and vaccinated twice. Efficacy was also analyzed for three age groups: 0-15, 16-64, and 65-104 years. Influenza-like illness (ILI) was diagnosed according to Ministry of Health (MWH, Labor and Welfare in Japan) criteria. Laboratory-confirmed influenza cases were analyzed separately. The respective vaccine efficacy in the 0-15 years group for the one- and two-dose regimens was 67.6 and 84.5% for ILI and 54.0 and 79.8% for laboratory-confirmed influenza. Influenza vaccination was also shown to be effective in subjects 16-64 years. Vaccine effectiveness was not able to be determined for the over 65 years group, probably due to an insufficient number of infected patients. These results suggest that influenza vaccination is effective for children and adults and that a two-dose regimen is superior to a single dose in children 0-15 years.