Effect of Eicosapentaenoic Acid/Docosahexaenoic Acid on Coronary High-Intensity Plaques Detected Using Noncontrast T1-weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study.

AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02).

OBJECTIVE: Rikkunshito, an herbal medicine, is widely prescribed in Japan for the treatment of anorexia and functional dyspepsia, and has been reported to recover reductions in food intake caused by cisplatin. We investigated whether rikkunshito could improve chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients treated with cisplatin. METHODS: Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m² day 1) and paclitaxel (135 mg/m² day 0) as first-line chemotherapy were randomly assigned to the rikkunshito group receiving oral administration on days 0-13 with standard antiemetics, or the control group receiving antiemetics only. The primary endpoint was the rate of complete control (CC: no emesis, no rescue medication, and no significant nausea) in the overall phase (0-120 hours). Two-tailed p<0.20 was considered significant in the planned analysis. RESULTS: The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group (57.9% vs. 35.3%, p=0.175), as were the secondary endpoints: the CC rate in the delayed phase (24-120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed phases (63.2% vs. 35.3%, p=0.095; 84.2% vs. 52.9%, p=0.042; 84.2% vs. 52.9%, p=0.042, respectively), and time to treatment failure (p=0.059). Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6. CONCLUSION: Rikkunshito provided additive effect for the prevention of CINV and anorexia.

Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity.

PURPOSE: Magnesium supplementation is an effective protective method against cisplatin-induced nephrotoxicity (CIN); however, there are few reports regarding the mechanism of its nephroprotective effect. The aim of this study was to determine whether premedication with intravenous magnesium prevents CIN and to determine the relationship between its nephroprotective effect and serum magnesium level. METHODS: Fifty-eight patients with head and neck cancer who received cisplatin, docetaxel, and 5-fluorouracil (DCF) were retrospectively investigated. Grade 2 or more serum creatinine elevation was defined as CIN. The incidence of CIN was compared between a magnesium sulfate (20 mEq, 2.46 g) premedication group and a non-magnesium group during the first cycle and in all cycles. RESULTS: CIN did not occur in any patients receiving magnesium premedication but did occur in 5 of 29 patients during the first cycle and in 6 patients during all subsequent cycles in patients who did not receive magnesium premedication. Furthermore, the variation of creatinine clearance was significantly worse in the non-magnesium group than in the magnesium premedication group from baseline. There was no difference in adverse effects or response rate between the two groups. Univariate analysis suggested that magnesium premedication significantly reduced the risk of CIN. On the other hand, serum magnesium depletion was seen in both groups to equal degrees despite supplementation. CONCLUSION: Intravenous magnesium premedication has a protective effect on cisplatin-induced nephrotoxicity without the influence on the serum magnesium level. Magnesium premedication is a simple nephroprotective method that does not influence other adverse effects or rate of response to chemotherapy.

Ultrafast excited-state dynamics of copper(I) complexes.

Bis-diimine Cu(I) complexes exhibit strong absorption in the visible region owing to the metal-to-ligand charge transfer (MLCT) transitions, and the triplet MLCT ((3)MLCT) states have long lifetimes. Because these characteristics are highly suitable for photosensitizers and photocatalysts, bis-diimine Cu(I) complexes have been attracting much interest. An intriguing feature of the Cu(I) complexes is the photoinduced structural change called "flattening". Bis-diimine Cu(I) complexes usually have tetrahedron-like D2d structures in the ground (S0) state, in which two ligands are perpendicularly attached to the Cu(I) ion. With MLCT excitation, the central Cu(I) ion is formally oxidized to Cu(II), which induces the structural change to the "flattened" square-planar-like structure that is seen for usual Cu(II) complexes. In this Account, we review our recent studies on ultrafast excited-state dynamics of bis-diimine Cu(I) complexes carried out using femtosecond time-resolved optical spectroscopy. Focusing on three prototypical bis-diimine Cu(I) complexes that have 1,10-phenanthroline ligands with different substituents at the 2,9-positions, i.e., [Cu(phen)2](+) (phen = 1,10-phenanthroline), [Cu(dmphen)2](+) (dmphen = 2,9-dimethyl-1,10-phenanthroline), and [Cu(dpphen)2](+) (dpphen = 2,9-diphenyl-1,10-phenanthroline), we examined their excited-state dynamics by time-resolved emission and absorption spectroscopies with 200 fs time resolution, observed the excited-state coherent nuclear motion with 30 fs time resolution and performed complementary theoretical calculations. This combined approach vividly visualizes excited-state processes in the MLCT state of bis-diimine Cu(I) complexes. It was demonstrated that flattening distortion, internal conversion, and intersystem crossing occur on the femtosecond-early picosecond time scale, and their dynamics is clearly identified separately. The flattening distortion predominantly occurs in the S1 state on the subpicosecond time-scale, and the precursor S1 state retaining the initial undistorted structure appears as a metastable state before the structural change. This observation indicates that the traditional understanding based on the Jahn-Teller effect appears irrelevant for realistically discussing the photoinduced structural change of bis-diimine Cu(I) complexes. The lifetime of the precursor S1 state significantly depends on the substituents in the three complexes, indicating that the flattering distortion requires a longer time as the substituents at 2,9-positions of the ligands become bulkier. It is suggested that the substituents are rotated to avoid steric repulsions to achieve the flattened structure at the global minimum of the S1 state, implying the necessity of discussion based on a multidimensional potential energy surface to properly consider this excited-state structural change. After the flattening distortion, the S1 states of [Cu(dmphen)2](+) and [Cu(dpphen)2](+), which have bulky substituents, relax to the T1 state by intersystem crossing on the ∼10 ps time scale, while the flattened S1 state of [Cu(phen)2](+) relaxes directly to the S0 state on the ∼2 ps time scale. This difference is rationalized in terms of the different magnitude of the flattening distortion and relevant changes in the potential energy surfaces. Clear understanding of the ultrafast excited-state process provides a solid basis for designing and using Cu(I) complexes, such as controlling the structural change to efficiently utilize the energy of the MLCT state in solar energy conversion.

Anti-allergic mechanisms of Japanese herbal medicine, yokukansan on mast cells.

We previously reported that the addition of orally administered yokukansan (YKS), a traditional Japanese herbal medicine, to the standard regimen using histamine H1-receptor inhibitors was effective in controlling refractory chronic urticaria, but the mechanism remained unknown. YKS has also been reported to be effective on inhibiting the development of atopic dermatitis-like skin lesions in NC/Nga mice. As known, the release of various chemical mediators including histamine from degranulated mast cells is strongly related to the mechanism of these diseases. Thus the purpose of this study was to examine the mechanisms behind the medicinal effects of YKS on mast cells using an in vitro system and rat basophil leukemia (RBL-2H3) cells. The degree of degranulation was measured by ß-hexosaminidase secretion assay and intracellular calcium influx assay. ELISA for cytokines (TNF-α and IL-4) was also conducted using cell culture media. Furthermore, we investigated the effects of YKS on the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokine production (IL-8) in human dermal microvascular endothelial cells using gene-transcriptional- and immunohisotoligical analysis. We found that YKS inhibited secretion of ß-hexosaminidase, intracellular calcium increase, production of TNF-α and ICAM-1 expression, and that several YKS ingredients may be the key effectors. In conclusion, YKS may suppress several mast cell functions such as degranulation and calcium increase that eventually inhibits the release of proinflammatory cytokines. Furthermore, YKS suppresses ICAM-1 expression on human microvascular endothelial cells. These findings may promote our understanding of the beneficial effects of YKS on mast cell-associated allergic diseases.

Coherent nuclear dynamics in ultrafast photoinduced structural change of bis(diimine)copper(I) complex.

The photoinduced structural change of a prototype metal complex, [Cu(dmphen)(2)](+) (dmphen = 2,9-dimethyl-1,10-phenanthroline), was studied by ultrafast spectroscopy with time resolution as high as 30 fs. Time-resolved absorption measured with direct S(1) excitation clearly showed spectral changes attributable to the D(2d) (perpendicular) → D(2) (flattened) structural change occurring in the metal-to-ligand charge transfer singlet excited state ((1)MLCT) and the subsequent S(1) → T(1) intersystem crossing. It was confirmed that the two processes occur with time constants of ~0.8 ps (structural change) and ~10 ps (intersystem crossing), and their time scales are clearly well-separated. A distinct oscillation of the transient absorption signal was observed in the femtosecond region, which arises from the coherent nuclear motion of the perpendicular S(1) state that was directly generated by photoexcitation. This demonstrated that the perpendicular S(1) state has a well-defined vibrational structure and can vibrate within its subpicosecond lifetime. In other words, the S(1) state stays undistorted in a short period, and the coherent nuclear motion is maintained in this state. Time-dependent density functional theory (TDDFT) calculations gave consistent results, indicating a very flat feature and even a local minimum at the perpendicular structure on the S(1) potential energy surface. The vibrational assignments of the S(1) nuclear wavepacket motion were made on the basis of the TDDFT calculation. It was concluded that photoexcitation induces a(1) vibrations containing the Cu-ligand bond length change and a b(1) vibration attributed to the ligand-twisting motion that has the same symmetry as the flattening distortion. Ultrafast spectroscopy and complementary quantum chemical calculation provided an overall picture and new understanding of the photoinduced structural change of the prototypical metal complex.

Beneficial effect of a diet containing heat-killed Lactobacillus paracasei K71 on adult type atopic dermatitis.

The purpose of this study was to investigate the clinical effect of a supplementary diet containing heat-killed lactic acid bacterium Lactobacillus paracasei K71 (LAB diet) on adult patients with atopic dermatitis (AD). A randomized, double-blind, placebo-controlled study was conducted in 34 adult type AD subjects who were treated with conventional topical corticosteroid and tacrolimus. LAB diet or placebo was added over 12 weeks. The primary end-point was the clinical severity of AD which was evaluated by a severity scoring system proposed by the guideline of the Japanese Dermatological Association. The effect was also secondarily evaluated by itch scores of visual analog scales (VAS), quality-of-life (QOL) impairment scores of Skindex 16 and consumption amounts of topical therapeutics. Data on these four assessment variables were collected at baseline and at week 4, 8 and 12. Within the study population, the skin severity scores were significantly decreased from baseline at week 8 (P<0.05) and at week 12 (P<0.01) in the LAB diet group but not in the placebo group. Influence of LAB diet on itch scores or QOL impairment scores was not evident. The consumption of topical therapeutics in the placebo group was 1.9-times greater in total amount compared with the corresponding value in the LAB diet group during the intervention period, although there was no significant difference. No LAB diet- or placebo-related adverse events were observed. We concluded that the LAB diet may have some benefits as a complementary therapy for adult AD patients who are managed with the conventional treatment.

Efficacy and Safety of a Traditional Herbal Medicine, Hochu-ekki-to in the Long-term Management of Kikyo (Delicate Constitution) Patients with Atopic Dermatitis: A 6-month, Multicenter, Double-blind, Randomized, Placebo-controlled Study.

Hochu-ekki-to is a traditional herbal (Kampo) medicine that has been shown to be effective for patients with Kikyo (delicate, easily fatigable, or hypersensitive) constitution. Previous case reports have suggested that this herbal drug was effective for a certain subgroup of patients with atopic dermatitis (AD). We aimed to evaluate the efficacy and safety of Hochu-ekki-to in the long-term management of Kikyo patients with AD. In this multicenter, double blind, randomized, placebo-controlled study, 91 Kikyo patients with AD were enrolled. Kikyo condition was evaluated by a questionnaire scoring system. All patients continued their ordinary treatments (topical steroids, topical tacrolimus, emollients or oral antihistamines) before and after their protocol entry. Hochu-ekki-to or placebo was orally administered twice daily for 24 weeks. The skin severity scores, total equivalent amount (TEA) of topical agents used for AD treatment, prominent efficacy (cases with skin severity score = 0 at the end of the study) rate and aggravated rate (more than 50% increase of TEA of topical agents from the beginning of the study) were monitored and evaluated. Seventy-seven out of 91 enrolled patients completed the 24-week treatment course (Hochu-ekki-to: n = 37, placebo: n = 40). The TEA of topical agents (steroids and/or tacrolimus) was significantly (P < 0.05) lower in the Hochu-ekki-to group than in the placebo group, although the overall skin severity scores were not statistically different. The prominent efficacy rate was 19% (7 of 37) in the Hochu-ekki-to group and 5% (2 of 40) in the placebo group (P = 0.06). The aggravated rate was significantly (P < 0.05) lower in the Hochu-ekki-to group (3%; 1 of 37) than in the placebo group (18%; 7 of 39). Only mild adverse events such as nausea and diarrhea were noted in both groups without statistical difference. This placebo-controlled study demonstrates that Hochu-ekki-to is a useful adjunct to conventional treatments for AD patients with Kikyo constitution. Use of Hochu-ekki-to significantly reduces the dose of topical steroids and/or tacrolimus used for AD treatment without aggravating AD.

Feasibility of oxaliplatin and infusional fluorouracil/leucovorin (FOLFOX4) for Japanese patients with unresectable metastatic colorectal cancer.

BACKGROUND: A combination of oxaliplatin and infusional fluorouracil/leucovorin (FOLFOX4) is one of the standard regimens for palliative and adjuvant chemotherapy for colorectal cancer. However, the feasibility of FOLFOX4 for Japanese patients has not been determined. We conducted this prospective study to evaluate the feasibility of FOLFOX4. METHODS: Previously treated or untreated patients with unresectable metastatic colorectal cancer were enrolled. The primary endpoint was the rate of completion which was defined as completion of the first 4 cycles with relative dose-intensity of oxaliplatin of 80% or higher. RESULTS: Of the 32 enrolled patients, 31 received FOLFOX4. Twenty-four patients (75%) had received prior chemotherapy. The rate of completion of the first four cycles was 87% (27/31; 95% CI, 70.2-96.4%). With the median number of cycles of nine (range, 1-26), grade 3 or 4 hematological toxicity and non-hematological toxicity were seen in 12 (39%) and 5 (16%) patients, respectively. Grade 1 or 2 sensory neuropathy was seen in 28 patients (90%), but no grade 3 or 4 neuropathy was seen. Grade 1 or 2 allergic reaction was seen in five patients (16%). One patient developed fatal interstitial pneumonitis and died of respiratory failure. Objective response rate was 28.6% (6/21; 95% CI, 11.3-52.2%) in the patients with measurable lesions. Median progression-free survival was 6.5 months (95% CI, 4.6-8.5 months) in all patients. CONCLUSIONS: The completion rate of the first four cycles was as high as expected with manageable toxicity, although fatal pneumonitis developed in one case. FOLFOX4 is feasible for Japanese patients.

Adjuvant chemotherapy with irinotecan hydrochloride and cisplatin for clear cell carcinoma of the ovary.

Clear cell carcinoma (CCC) of the ovary has distinct characteristics showing resistance to conventional platinum-based regimen. Our aim was to evaluate the effects of combination therapy with irinotecan hydrochloride and cisplatin (CPT-P), comparing to regimen with paclitaxel and platinum (TP). We retrospective reviewed 172 patients with complete surgical staging procedures including lymphadenenctomy. Forty-six patients received CPT-P and 126 patients were treated with TP. Survival of the two groups was compared. Between CPT-P group and TP group, there was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, and follow-up period. There was no significant difference in progression-free survival of patients with stage I tumors (p=0.95) and suboptimally debulked stage II-IV tumors (p=0.92). Although there was no significant difference of overall survival, progression-free survival of CPT-P group was significantly better than that of TP group in optimally debulked stage II-IV (p=0.03). Multiple regression survival analysis revealed CPT-P regimen (p=0.02) and residual tumor diameter (p<0.01) were both independent prognostic factors in stage II-IV tumors. The combination of CPT-P was shown to have a potential therapeutic benefit for advanced CCC of the ovary, especially for cases with optimal debulking surgery. However, this is a limited retrospective study, therefore we recommend that the CPT-P regimen be evaluated in a larger prospective study.