NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min À1 . The starting dose was 6 mg DXR equivalent m À2 , and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m À2 . Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m À2 (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C 5 min and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m À2 every 3 weeks.

Raman spectra of p-cresol, a model compound for tyrosine, were measured in solutions of various solvents, paying special attention to the effects of hydrogen bonding on the Raman bands in the 1300-1150 cm-' region. The frequency of the v,,,. (C-O stretch) band was found to be sensitive to the state of hydrogen bonding at the phenolic hydroxyl group. It occurs at 1275-1265 cm-' in protondonating states, 1240-1230 cm-' in proton-accepting states and around 1255 cm-' in weakly or non-hydrogen-bonding states. This relationship between the v7,,. frequency and hydrogen bonding was verified in the Raman spectra of L-tyrosine and its derivatives in the crystalline state. Analysis of the crystal Raman spectra further suggested that the v7,, (C-C stretch) frequency also serves as a marker, though less sensitive, of hydrogen bonding and the v9,, (C-H bend) frequency reflects the displacement of the OH hydrogen atom from the plane of benzene ring, which may be induced by hydrogen bonding. These Raman bands are strong with UV excitation and are expected to be useful in characterizing tyrosine side-chains in peptides and proteins by UV resonance Raman spectroscopy.

The ambulatory blood pressure had a stronger predictive power for mortality than did the screening blood pressure. This appears to have been the first study of the prognostic significance of ambulatory blood pressure monitoring versus screening blood pressure measurements in a general population.

No abstract

The purpose of this study was to propose reference values, from a viewpoint of prognostic significance, for blood pressure (BP) measured at home with a semiautomated device (home BP measurement) to differentiate normotension and hypertension. We obtained home BP measurements for 1,913 population-based subjects aged 40 years and over in a rural Japanese community and followed up their survival for a mean duration of 5.0 years. There were 141 deaths during the follow-up period. The association between baseline BP values and the overall mortality was examined by Cox proportional hazards regression model, adjusted for age, gender, and the use of antihypertensive medication. The results indicated that the predictive power of home BP level for subsequent mortality was stronger than that of casual screening BP. There was a linear association between home systolic BP and mortality. The association between home diastolic BP and mortality was nonlinear and well approximated with the secondary degree equation of diastolic BP values. Based on this relation, we propose that the reference value for hypertension is 137/84 mm Hg, and normotension is below 137 mm Hg for home systolic BP and between 66 and 83 mm Hg for home diastolic BP. Home diastolic BP below 66 mm Hg should be considered as low diastolic blood pressure. In this population, home systolic BP of 137 mm Hg and home diastolic BP of 84 mm Hg corresponded to the 80th and 87th percentiles, respectively. Then, 29% of the subjects were classified as having hypertension, 52% as normotension, and 19% as low diastolic blood pressure. All previous studies proposing reference values for home BP measurement, derived from cross-sectional observations, were based on the statistical distribution of home BP values. The reference value must, however, be the one that best predicts the risk for morbidity and mortality from hypertension-related complications. This is the first report proposing reference values for home BP measurement based on prognostic criteria.

An extract of the crude drug "ukon", the rhizomes of Curcuma longa, exhibited intense preventive activity against carbon tetrachioride-induced liver injury in vivo and in vitro. The extract was subjected to frac-Part 8 in Liver-protective drugs. This paper also constitutes Part 53in the series on the validity of the Oriental medicines. Table I tionation by monitoring the activity by the in vitro assay methods employing carbon tetrachioride-and galactosamine-produced cytotoxicity in primary cultured rat hepatocytes. Curcuminoids were shown to possess significant antihepatotoxic action. The liverprotective effects of some analogues of ferulic acid and p-coumaric acid, probable metabolites of the curcuminoids, were also evaluated.

No abstract

We compared the reproducibility over time of blood pressure measured at the health examinations (screening blood pressure) and blood pressure measured at home (home blood pressure). Both screening and home blood pressure were measured in subjects of a rural community. Subjects measured their own blood pressure at home once in the morning using a semiautomatic oscillometric blood pressure measuring device at least three times (on at least 3 days) in each of two 4-week periods separated by one year. Similarly, two screening blood pressure measurements were obtained from the subjects at each of two health examinations also taken 1 year apart. A total of 136 untreated subjects without cardiovascular complications (40 men and 96 women, 56 +/- 11.7 years, mean +/- SD) were analyzed in the study. The correlations between the first and second blood pressure measurements of the subjects were significantly higher for the home blood pressure measurements (systolic: r = 0.844 and diastolic: r = 0.830) than for the screening blood pressure measurements (systolic: r = 0.692 and diastolic: r = 0.570). The mean differences between the first and second home blood pressure (0.8 +/- 7.7 mm Hg for systolic BP and 0.9 +/- 5.5 mm Hg for diastolic BP) were significantly smaller than those for the screening blood pressure (-3.9 +/- 13.8 for systolic BP and -3.1 +/- 10.2 for diastolic BP) (P < .001 for both comparisons), suggesting that the reproducibility of home blood pressure over time is superior to that of screening blood pressure. Such reliable blood pressure measurements obtained at home have a clinical significance for the diagnosis and treatment of hypertension and as a tool for evaluating the efficacy of antihypertensive drugs. Home blood pressure measurements also may be more useful than screening blood pressure measurements in predicting future cardiovascular events.