In a phase I clinical trial, it is essential to scientifically distinguish abnormal variation from biological variation in laboratory test results observed in healthy volunteers. However, no evidence-based standard for this has been established to date. We propose a formula that can distinguish abnormal variation from biological variations based on the Reference Change Value, which is calculated from analytical and within-subject biological variation. By using our formula, it is possible to objectively evaluate the effects of the test drug on the volunteer.

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To examine the effect of controlled-release nifedipine (nifedipine CR) given at bedtime on morning hypertension and to compare its effect with that of α-adrenergic blocker, doxazosin, given at bedtime, we performed a cross-over study in ten (5 males, 5 females) hypertensive patients with morning hypertension. After control measurements, the patients were assigned to either nifedipine CR (20-40 mg) first or doxazosin (1-2 mg) first. After 4 weeks of the treatment, measurements were repeated and medication was switched to another drug for another 4 weeks. Systolic and diastolic blood pressure (BP) and heart rate were measured using a 24-hour ambulatory BP monitoring system. While BP at evening and early nighttime (16 : 00-3 : 00) were the same in the three conditions (control, nifedipine CR, and doxazosin), nifedipine CR significantly suppressed BP at the latest nighttime (5 : 00-6 : 00) (systolic BP/diastolic BP : control 128.4±12.0/85.1±10.6 mmHg, doxazosin 124.5±11.6/81.4±10.7 mmHg, nifedipine CR 111.2±16.0/77.7±11.2 mmHg, p<0.01 control vs nifedipine CR, p<0.05 doxazosin vs nifedipine CR). Nifedipine CR also suppressed BP at the morning (6 : 30-9 : 30) (control 144.2±11.2/92.2±12.2 mmHg, doxazosin 137.2±8.4/87.1±11.1 mmHg, nifedipine CR 123.9±10.8/83.1±12.1 mmHg, p<0.02 control vs nifedipine CR, p<0.01 nifedipine CR vs doxazosin). There was a significant increase in heart rate only in the doxazosin group during sleep time (control 64.7±5.2/min, doxazosin 68.5±8.8/min, nifedipine 64.5±5.7/min, p<0.05 doxazosin vs nifedipine). These results indicate that the dose of nifedipine CR that does not affect BP from evening through early morning, administered before sleep, is effective in the treatment of morning hypertension.

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Aims : The aim of this study was to investigate the effects of sex and age on QT/QTc interval in healthy Japanese males and females. In addition, we investigated the difference in the evaluations between manual read and automatic read standard 12-lead electrocardiography (ECG).
Methods : In the present study 309 subjects (175 males, 134 females, age : 20-78 years), who had undergone clinical laboratory tests including ECG, physical examination and biochemical blood test in Kan-nondai clinic were enrolled. ECG measurement was made by a Mortara ELI 250 ECG, and the ECG was performed three times every minute for each subject. Electronic ECG data (chart paper) was sent to the outside evaluating system of eResearch Technology Inc. for the manual read. QT/QTc interval data were corrected as QTcB (Bazett's correction) and QTcF (Fridericia correction) and were evaluated according to factors including gender and age. In addition, QT/QTc intervals were compared between manual read and automatic read ECG.
Results : The QTcB and QTcF were significantly longer in females (425±18 msec, 421±15 msec, respectively) than males (407±24 msec, 405±20 msec, respectively) in the present enrolled subjects (p<0.0001 in both QTcB and QTcF). The corrected QT/QTc tended to be correlated with age, and slightly positive, in both male and female subjects, although the correlation was marginally significant for QTcB in males. From actual observation ECG parameters calculated from the manual read were shorter than those from the automatic read (% of manual<automatic read : 87.5% for QT, 80.5% for QTcB and 84.7% for QTcF). The measurement deviation of the parameters was 15±10 msec for QTcB and 12±10 msec for QTcF.
Conclusions : These results suggested that a ECG parameters study covering a wide range of males and females should be required for developmental drugs with the potential to induce QT/QTc prolongation.

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Staphylococcus aureus (S. aureus) producing superantigens (SAgs), such as staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1) are frequently observed in atopic dermatitis (AD). However, few studies have been carried out to disclose the association of immune responses to SAgs and the therapeutic response to immunosuppressive drugs in AD. Therefore, we investigated the prevalence and role of SAgs on the pathophysiology and immunosuppressive drug-sensitivity in AD patients. We classified 29 patients into two groups on the basis of their clinical AD scores : the low-score group (n=14) corresponding to mild patients and the high-score group (n=15) corresponding to severe patients. We analyzed the plasma anti-SEB-or TSST-1-IgE level of these patients and healthy subjects by ELISA. We estimated individual drug-sensitivity by determining the drug concentrations that would give 50% inhibition (IC₅₀) of peripheral blood mononuclear cell (PBMC) proliferation in vitro. The levels of plasma anti-SEB- and TSST-1-IgE in the severe patients were significantly higher than those in the mild patients (p<0.05 and p<0.05, respectively). When stimulated with concanavarin A (ConA) in vitro, PBMCs in the severe patients exhibited a low sensitivity to suppressive efficacy of tacrolimus as compared to the mild patients (p<0.01). Furthermore, there was a significant correlation between the IC₅₀s of tacrolimus and plasma anti-TSST-1-IgE levels (p<0.01). We showed that PBMCs in severe AD patients exhibited a lower sensitivity to tacrolimus, and had higher plasma levels of anti TSST-1-IgE as compared to mild AD patients. SAgs appear to be one of the causes of decreased PBMC sensitivity to tacrolimus, and therefore, alternative treatment might be useful if considered according to the individual drugsensitivity data and anti-TSST-1 IgE levels.

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