Efficacy and safety of luliconazole 5% nail solution for the treatment of onychomycosis: A multicenter, double-blind, randomized phase III study.

Onychomycosis is a highly prevalent and intractable disease. The first-line treatment agents are oral preparations, but an effective topical medication has long been desired. The objective was to investigate the efficacy and safety of luliconazole 5% nail solution, an imidazole antifungal agent, for the treatment of patients with onychomycosis. A multicenter, double-blind, randomized phase III study was conducted in Japanese patients with distal lateral subungual onychomycosis affecting the great toenails, with 20-50% clinical involvement. Patients were randomized (2:1) to luliconazole or vehicle once daily for 48 weeks. The primary end-point was the complete cure rate (clinical cure [0% clinical involvement of the nail] plus mycological cure [negative results on direct microscopy]). The adverse event incidence was monitored to evaluate safety. The complete cure rate significantly favored luliconazole (14.9%, 29/194 subjects) versus vehicle (5.1%, 5/99) (P = 0.012). Similarly, the negative direct microscopy rate was significantly higher with luliconazole (45.4%, 79/174) than with vehicle (31.2%, 29/93) (P = 0.026). There were no serious adverse drug reactions. We conclude that once daily topical luliconazole 5% nail solution demonstrated clinical efficacy and was confirmed to be well tolerated.

Indices of initial hepatitis C virus RNA reduction rate to predict efficacy of interferon-beta followed by peginterferon plus ribavirin for genotype 1b high viral load.

AIM: Initial hepatitis C virus (HCV) RNA reduction was investigated as a potential index for sustained virological response (SVR) in the treatment of interferon (IFN)-ß followed by peginterferon plus ribavirin (PEG IFN/RBV). METHODS: The treatment course was retrospectively analyzed in 64 genotype 1b patients with a HCV RNA level of 5.0 logIU/mL or higher. IFN-ß was administrated twice a day for 2 weeks followed by 24 or 48 weeks of PEG IFN/RBV. The serum HCV RNA level was measured by real-time polymerase chain reaction before administration and at 1, 2 and 4 weeks of therapy. RESULTS: By the duration of PEG IFN administration, the SVR rates were 11% (2/18, <19 weeks), 64% (23/36, 20-24 weeks) and 40% (4/10, 25-72 weeks) (P = 0.0011, χ(2) -test). The SVR rate was high in patients in whom the HCV RNA level had decreased by 2.5 logIU/mL or greater at 1 week of IFN-ß (29/55 [53%] vs 0/9 [0%], P = 0.0029, χ(2) -test). Among these patients, the SVR rate was even higher in those with continuous reduction in the first 2 weeks after the switch to PEG IFN/RBV (27/45 [60%] vs 2/10 [20%], P = 0.0048). Age below 65 years, no previous IFN course and good initial HCV RNA reduction were significantly associated with SVR on multivariate analysis, and the SVR rate was 95% (18/19) among these patients. CONCLUSION: The 2.5 logIU/mL reduction in HCV RNA at 1 week of IFN-ß and the continuous reduction just after the switch to PEG IFN/RBV are important SVR-predictive indices.

Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management.

Variant angina is a form of angina pectoris that shows transient ST-segment elevation on electrocardiogram during an attack of chest pain. Ischemic episodes of variant angina show circadian variation and often occur at rest from midnight to early morning. Ischemic episodes also occur during mild exercise in the early morning. However, they are not usually induced by strenuous exercise in the afternoon. Other important clinical features of variant angina include the high frequency of asymptomatic ischemic episodes and the syncope that sometimes occur during the ischemic episodes. Syncope is due to severe arrhythmias, including ventricular tachycardia, ventricular fibrillation, and high-degree atrioventricular block. Coronary artery spasm is the mechanism of ischemic episodes in variant angina. The incidence of coronary artery spasm shows a racial difference and is higher in Japanese than in Caucasians. Coronary arteriograms are normal or near-normal in most Japanese patients with variant angina. Deficient basal release of nitric oxide (NO) due to endothelial dysfunction, and enhanced vascular smooth muscle contractility with the involvement of the Rho/Rho-kinase pathway are reported to play important roles in the pathogenesis of coronary artery spasm. Other precipitating factors of coronary artery spasm include imbalance in autonomic nervous activity, increased oxidative stress, chronic low-grade inflammation, magnesium deficiency, and genetic susceptibility. The genetic risk factors associated with coronary artery spasm include gene polymorphisms of endothelial NO synthase (NOS), paraoxonase, and other genes. Calcium channel blockers are extremely effective in preventing coronary spasm. The long-acting nitrate, nicorandil, and Rho-kinase inhibitor are also useful for inhibiting coronary artery spasm. Because variant angina can lead to acute myocardial infarction, fatal arrhythmias, and sudden death, early treatment is important. The prognosis of patients with variant angina is favorable, if early complications can be overcome. However, because coronary artery spasm cannot be suppressed in some patients, even with multiple medications, medications to suppress intractable coronary artery spasm must be developed.

[A case of rapid-onset antimitochondrial antibody-positive autoimmune hepatitis possibly triggered by a urinary tract infection].

A 54-year-old woman suffered acute hepatitis after she acquired cystitis. Laboratory results on admission showed: AST 925, ALT 1171, ALP 623, gamma-GTP127 IU/l, T-Bil 5.0 mg/dl, antinuclear antibodies negative, smooth muscle antibodies 80, antimitochondrial antibodies (AMA) 80, antimitochondrial M2 antibody (AMA-M2) 117 index, IgG 2210 mg/dl. She also had HLA-DR4 and HLA-DR8. Histological study of a liver biopsy specimen suggested that she had autoimmune hepatitis rather than primary biliary cirrhosis. When prednisolone was administered, her liver function immediately improved and AMA and AMA-M2 levels fell to 20 and 52 respectively. However when cystitis recurred 4 months later, her liver function worsened. Laboratory findings showed AST 174, ALT 183 IU/l. Upon increasing the dosage of prednisolone, her liver function improved again. After the recurrence of hepatitis, AMA and AMA-M2 levels increased to 320 and 149 respectively. We speculate that the urinary tract infection triggered an autoimmune response and her genetic predisposition also played a crucial role in the process.

Administration of the Rho-kinase inhibitor, fasudil, following nitroglycerin additionally dilates the site of coronary spasm in patients with vasospastic angina.

BACKGROUND: The Rho/Rho-kinase signaling pathway is known to be involved in the pathogenesis of coronary artery spasm. Previous studies reported the efficacy of the Rho-kinase inhibitor, fasudil, in the prevention and relief of coronary spasm. The usefulness of fasudil in combination with conventional vasodilating agents, however, has not been fully examined in patients with vasospastic angina. METHODS AND RESULTS: A total of 26 patients (mean age, 61+/-11 years) with documented vasospasm in the left anterior descending coronary artery were examined by the acetylcholine stress test. Coronary diameter at the spasm site was measured at baseline and after the administration of vasodilator agents in the following order: intracoronary nitroglycerin (NTG) (300 microg), intravenous fasudil (30 mg, n=15, fasudil group) or saline (n=11, saline group), and again NTG during coronary angiography. The increase in diameter observed following the first NTG administration was found to be similar in the fasudil and saline groups (38.3+/-23.5% and 42.3+/-17.1%, respectively). The additional change in diameter on fasudil treatment (16.9+/-11.2% increase over the diameter after the first NTG administration) was significantly larger than that with saline (-2.8+/-7.6%, P<0.001). The second administration of NTG did not affect the diameter of the spasm site in either group. CONCLUSIONS: Fasudil further dilated the site of coronary spasm, which had already been treated with NTG in patients with vasospastic angina. These findings support and extend the previous results that showed the feasibility of employing fasudil as a novel therapeutic approach for coronary spasm.

Relationship between the mismatch of 123I-BMIPP and 201Tl myocardial single-photon emission computed tomography and autonomic nervous system activity in patients with acute myocardial infarction.

The purpose of this study was to elucidate the relationship between the mismatch of thallium-201(Tl) and iodine-123-beta-methyl-iodophenyl-pentadecanoic acid (BMIPP) myocardial single-photon emission computed tomography (SPECT) and autonomic nervous system activity in myocardial infarction (MI) patients. The subjects were 40 patients (34 males, 6 females) who underwent examinations by 123I-BMIPP and 201Tl myocardial SPECT imaging and 24-hour Holter monitoring within a 3-day period 3 weeks after the onset of their first MI. R-R intervals were analyzed every hour over a period of 24 hours by fast Fourier transformation (FFT). High frequency (HF) and low frequency (LF) were defined as markers of cardiac vagal activity in the former and the LF/HF ratio as sympathetic activity. Greater or more extensive decreases in the BMIPP image than that in the Tl image were defined as a positive mismatch. Patients were divided into positive and negative mismatch groups of 20 patients each. There were no significant differences between the 2 groups in age, sex, site of infarction, max CK (creatine kinase), max CK-MB, or left ventricular ejection fraction. The incidences of clinical signs suggesting residual myocardial ischemia were significantly greater in the positive than in the negative mismatch group (P < 0.05). The mean values for HF over the entire 24-hour period and over the 5-hour nocturnal period (0-5 AM) in the positive mismatch group were both significantly lower than those in the negative mismatch group (P < 0.001 in both groups). The 24-hour mean HF and mean nighttime HF in patients with signs of residual ischemia were both significantly lower than in those without signs of residual ischemia in the positive mismatch group (P < 0.05 in both groups). The mean LF/HF ratio for both the entire 24-hour and the nocturnal period in the positive mismatch group were significantly higher than those in the negative mismatch group (P < 0.001, P < 0.05, respectively). The daily profile of hourly HF measurements was significantly lower in the positive mismatch group than in the negative mismatch group (P < 0.02). The mean values of HF for 24-hour and 5-hour periods were significantly lower in patients with signs of residual ischemia in the positive mismatch group than in those with signs of residual ischemia in the negative mismatch group (P < 0.01, P < 0.02, respectively). There were no significant differences between the patients with signs of residual ischemia in the negative mismatch group and those without signs of residual ischemia in the positive and negative mismatch group with regard to the mean values of HF and the LF/HF ratio measured every hour for 24 hours and 5 hours. It is concluded from the present study that the findings of a mismatch on 123I-BMIPP and 201Tl myocardial SPECT 3 weeks after a first acute myocardial infarction with uncomplicated moderate or severe heart failure and decreased heart rate variability are related to residual myocardial ischemia. A combined assessment of heart rate variability in 24-hour Holter ECG monitoring and perfusion-metabolism mismatch in 123I-BMIPP and 201Tl myocardial SPECT is useful for determining residual myocardial ischemia in the follow-up of those with acute myocardial infarction.

Vasodilatory effect of subsequent administration of fasudil, a rho-kinase inhibitor, surpasses that of nitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris.

BACKGROUND: Recent studies have suggested that the Rho/Rho-kinase mediated pathway (Rho-kinase pathway) regulates the vasomotion of arteries in pathological conditions. However, it remains unclear regarding whether this pathway regulates the coronary vasomotion of atherosclerotic lesions. METHODS AND RESULTS: The coronary diameter at the concentric stenotic site, which is considered to reflect the whole circumferential atherosclerosis, in patients with stable angina pectoris (SAP; n=11) and the control site in patients with SAP and chest pain syndrome (CPS; n=9), was measured at baseline and after the intracoronary administration of nitroglycerin (200 microg) and the subsequent intravenous infusion of fasudil (30 mg for 30 min), a Rho-kinase inhibitor, during coronary angiography. The change in the diameter with fasudil at the concentric stenotic site (22.0+/-10.0%) was significantly higher than that with nitroglycerin (4.7+/-6.0%, p<0.001) in patients with SAP. Meanwhile, the vasodilatory effect of nitroglycerin and fasudil at the control site was similar in both group of patients (25.5+/-17.3% and 21.9+/-14.9% in SAP and 34.4+/-20.8% and 33.2+/-23.6% in CPS, respectively). CONCLUSIONS: The vasodilatory effect of the subsequent administration of fasudil surpassed that of nitroglycerin at the concentric coronary stenosis in patients with SAP, thus suggesting that the Rho-kinase pathway regulates the coronary vasomotion of atherosclerotic lesions.

Pharmacological preconditioning with bradykinin affords myocardial protection through NO-dependent mechanisms.

Bradykinin (BK) is one of the triggers of ischemic preconditioning. Protein kinase C (PKC) and mitochondrial ATP-dependent potassium (K(ATP)) channels are central factors in cardioprotection afforded by BK. However, the role of nitric oxide (NO) in the early phase protection of preconditioning with BK is not well understood. We assessed the signaling pathway of the early phase protection of pharmacological preconditioning afforded by BK. Isolated perfused rat hearts (n = 8/group) were subjected to 30-minute global ischemia and 50-minute reperfusion. Left ventricular systolic pressure (LVSP) was recorded prior to the global ischemia and at the end of reperfusion. Preconditioning with BK was induced by two cycles of 5-minute infusion of BK (0.5 micromol/L) and 5-minute washout prior to the global ischemia. To examine participants in the signaling pathway, 5-hydroxydecanoate (5-HD, 200 micromol/L), chelerythrine (CH, 5 micromol/L), or N(omega)-nitro-L-arginine methyl ester (L-NAME, 50 mmol/L) was added to the perfusate for 5 minutes prior to the infusion of BK. Pharmacological preconditioning by BK improved postischemic recovery of LVSP (+ 45.1% versus control, P < 0.01). Protection by BK was abolished by coadministration of CH, 5-HD, or L-NAME. BK affords myocardial protection in the early phase of pharmacological preconditioning through a pathway that includes endogenous NO, PKC, and mitochondrial K(ATP) channels.

Is angiotensin-converting enzyme inhibitor useful in a Japanese population for secondary prevention after acute myocardial infarction? A final report of the Japanese Acute Myocardial Infarction Prospective (JAMP) study.

BACKGROUND: Although angiotensin-converting enzyme (ACE) inhibitors have appeared to be useful for secondary prevention after acute myocardial infarction (AMI) in Western countries, that has not been confirmed in non-western countries. We investigated whether ACE inhibitors improve survival rates in patients who have survived an AMI in Japan. METHODS: A randomized controlled trial, the first non-pharmaceutical company-supported multicenter trial of a medication in Japan, was carried out in 48 institutions from 1993 to 2000. A total of 888 of 1163 patients with AMI were eligible for the full analysis set (FAS). The mean patient age was 62 years, and 78% of patients were men. Subjects were randomized to 2 groups; 422 received ACE inhibitors and 466 did not receive ACE inhibitors. The primary end point was combined cardiac events, which was defined as cardiac or non-cardiac death, recurrent non-fatal myocardial infarction, coronary revascularization, and hospitalization because of worsening angina or congestive heart failure. The mean follow-up period was 5.8 years. RESULTS: There were no significant differences in the 2 groups in baseline data. During the follow-up period, 3 patients were lost to follow-up. With Kaplan-Meier analysis, the annual rate of total cardiac events was 32% in both groups. After adjustment for clinical baseline data, ACE inhibitor administration was not revealed with Cox regression analysis to have a significant prognostic effect in our study. CONCLUSION: We did not show a significant improvement in outcome with ACE inhibitor administration in subjects who survived after AMI in a Japanese study population. Further evaluations with a larger population or in subjects who are at a higher risk for AMI are necessary to confirm our findings.

[Detection of myocardial ischemia by analysis of the shape of exercise-induced ST elevation in infarct-related leads].

OBJECTIVES: Possible mechanisms of exercise-induced ST elevation in infarct-related leads include ventricular dyskinesis, and myocardial ischemia in the infarct region. Detection of ischemia in viable myocardium in the infarct region is important to determine the therapeutic strategy. This study evaluated whether the analysis of the shape of exercise-induced ST elevation(convex or concave type) is useful to detect myocardial ischemia in the infarct region. METHODS: Ninety-eight patients (78 males, 20 females, mean age 59 +/- 10 years) with prior Q wave myocardial infarction underwent the treadmill exercise test. Patients were divided into three groups according to the exercise-induced ST changes: No ST-E group, 27 patients without ST changes; Concave ST-E group, 52 patients with concave type ST elevation; Convex ST-E group, 19 patients with convex type ST elevation. Coronary arteriography was evaluated in all patients. Dobutamine stress echocardiography was performed in 38 patients, including 28 patients in the Concave ST-E group and 10 patients in the Convex ST-E group. Biphasic or worsening response on dobutamine stress echocardiography was defined as ischemic response. RESULTS: Coronary arteriography revealed significant stenosis of the infarct-related artery in 30% of the No ST-E group, 47% in the Convex ST-E and 86% in the Concave ST-E groups (p < 0.05). Dobutamine stress echocardiography revealed myocardial ischemia in the infarct region in 30% in the Convex ST-E group and 75% in the Concave ST-E group(p < 0.05). CONCLUSIONS: The Concave ST-E group had a higher incidence of stenosis of the infarct-related artery and myocardial ischemia in the infarct region. Analysis of the shape of exercise-induced ST elevation in infarct-related leads is useful for the detection of ischemia of viable myocardium.