To study the pharmacokinetics (PK) of flecainide acetate (FLC) and its suppressive effects on ventricular premature contractions (VPCs), twelve patients with frequent VPCs were studied following a single intravenous administration method. Either 1.0, 1.5, or 2.0 mg/kg of FLC was administered to each patient over 10 min and their blood samples were drawn before and at 10, 15, 30 min, and 1, 2, 4, 8, and 24 hr after the drug administration to measure the plasma drug concentration using high performance liquidchromatography. Standard 12 lead ECG and 24-hr dynamic ECG were recorded to assess the drug effects on VPCs and ECG parameters. Population PK/PD analysis was utilized to define the relationship between drug effect and concentration of FLC. Population PK parameters were obtained using a two-compartment model by NONMEM. The rate constant for elimination from central (k₁₀) for transfer, from central to peripheral (k₁₂), and from peripheral to central (k₂₁) (coefficient of variance of inter-individual variability) were 0.784 hr^-1, 15.8 hr^-1 (CV: 34.8%), and 1.13 hr^-1 (CV: 41.6%), respectively. The distribution volume of the central compartment was 475 ml/kg (CV: 24.0%) and the half-life in the elimination phase was 13.8 hr and the total clearance was 6.2 ml/kg/min.
The suppressive effects on VPCs were assessed in 8 patients with more than 5000 VPCs/day observed before the drug administration (control). Flecainide was effective in 7 out of 8 patients and we obtained the population PD parameters by employing asigmoid E_max model using individual PK parameters and % changes of VPCs/min compared with the control value. The equilibration rate constant, keo, was 3.39 hr^-1 (CV: 105%). The drug concentration that suppresses VPC at 50% of the control value in the effect compartment, Ce₅₀, was estimated to be 217 ng/ml (CV: 51.3%) which was almost the same as the minimum effective plasma drug concentration of FLC obtained from our previous study of oral administration method, and the sigmoid factor was 15.0. The equilibration half-time, t_1/2keo, was 12.3 min and indicating hysteresis between the plasma drug concentration and the onset of the drug effect.
Blood pressure or ECG parameters did not change significantly after the drug administration. No serious adverse effects were found in any patients.
In conclusion, the population PK/PD method with NONMEM is useful to establish a therapeutic protocol for the intravenous administration of FLC and is also useful to understand the hysteresis of the drug effect on the basis of the population PK/PD parameters.

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Depending on the administration method, the highly effective therapeutic concentrations (VSC: variable serum concentration) of theophylline can be attained only in the time range of frequent asthma attack. We used an oral sustained-release theophylline preparation in seven patients with bronchial asthma (2 males and 5 females ; mean age: 38.7 years) who had required more than 3 admissions per year, because of bronchial asthma attack despite being treated with Round-The-Clock (RTC) therapy of theophylline and inhalation of steroid. We examined the annual frequency of admissions and the.peak expiratory flow rate (PEFR) in remission.
Even though no difference was noted in serum concentrations of theophylline in the morning (the time range of attack) between RTC therapy and VSC therapy, the mean number of admissions during VSC therapy was 1.14 compared to 3.86 recorded during RTC therapy (p<0.001). PEFR in remission showed a significant improvement with VSC therapy compared to PEFR recorded during RTC therapy (p<0.05).
VSC therapy was proven to be useful for patients who failed to attain a favorable control of asthma attack by RTC therapy.

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The effect of nicardipine hydrochloride on casual blood pressure and 24-hour ambulatoryblood pressure, and pulse rate was studied. The effect obtained with tablets (20mg, t.i.d.) and sustained-release formulation (LA) (40 mg, b.i.d.) was compared by the crossover method in patients with essential hypertension.
1) Both systolic and diastolic casual blood pressures showed a significant decrease after administration of nicardipine tablets and LA. On the other hand, the pulse rateshowed nosignificant change.
2) In the 24-hour blood pressure monitoring, the antihypertensive effect of nicardipine LA on the systolic blood pressure tended to be stronger than that of nicardipine tablets. There were no significant differences in blood pressure level between the two drugs during the daytime. During the night, however, the antihypertensive effect of nicardipine LA on the systolic and diastolic blood pressures was significantly stronger than that of nicardipine tablets.
3) In the analysis of periodic regression curves, the levels were significantly reduced by nicardipine tablet and nicardipine LA as compared with the control period, while thepattern for nicardipine LA was similar to that in the control period rather than for nicardipine tablet.
We conclude that nicardipine tablets are useful for patients including the elderly in whom excessive nocturnal hypotension should be avoided. While nicardipine LA is useful for patients who need the nocturnal decrease in blood pressure and the suppression of the morning surge of blood pressure.

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Buserelin acetate, a gonadotropin-releasing hormone agonist (GnRH agonist), is widely used as a therapeutic agent for myoma uteri (MU). We investigated the standardtreatments for MU before and after the introduction of buserelin therapy by questionnaire given to gynecologists and according to official statistics. Based on our study, an economic analysis (cost analysis) was made using a tree model. The results indicated that: 1) the standard treatment for MU underwent a change after buserelin therapy became available, and 2) the therapeutic cost per patient with MU increased by a factor of 1.1-1.2. Finally, we discuss the justifiability of this cost increment based on the opinions of gynecologists who returned the questionnaire.

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