Purpose: The efficacy of a newly developed calcium antagonist, nicardipine hydrochloride, was evaluated to essential hypertension chronobiologically.
Methods: Thirteen patients with essential hypertension (7 male, 6 female; age range, 34-74yrs) were examined by the ambulatory blood pressure monitoring of Nippon Colin (Komaki, Japan). The monitoring was performed before the treatment for 48hr. Each patient was subsequently started on nicardipine hydrochloride twice daily for 1wk. The monitoring was repeated similarly thereafter. The least-square fit of a cosine with a period of 24hr was calculated to obtain MESOR, amplitude and acrophase. These data were evaluated comparing with chronodesm obtained from 334 Japanese in our laboratory.
Results and conclusions: 1) The drug was well tolerated. While blood pressure reduction was observed throughout the day, it was rather uniform and less reduced the blood pressure during night rest span and did suppress active span rise of the blood pressure. 2) This provided that the pharmacokinetic value showed a discrepancy from the pressure value and it could not predict the efficacy of the pressure reduction. 3) Therefore, the chronobiological evaluation of this drug was essential to start the antihypertensive therapy. Chronotherapy was imperative by this type of the therapy.

View full abstract

To adapt therapeutic drug monitoring to clinical practice, a pharmacokinetic and pharmacodynamic data analysis of the effects of diltiazem during treadmill tests in 22 patients with angina pectoris was performed. Scattered data obtained from the treadmill tests, pharmacokinetic parameters for diltiazem, indicators of diltiazem sensitivity, and plasma diltiazem concentrations, and effects at standard dose (60mg) were statistically analyzed, and their mutual relationships were examined by a correlation analysis and a multiple regression analysis. In addition, we derived predictive models for the effects of diltiazem from the results of the multiple regression analysis and then examined the predictive performance of these models. The patients' ages were correlated with plasma diltiazem concentrations, suggesting that plasma diltiazem concentration increases with increasing age for the same dose and after the same lapse time of following administration. On the other hand, plasma dilitiazem concentration was correlated with exercise time (Ext) at 3hr and with pressure-rate product during rest (RestPRP) at 1.5 or 3hr after administration, but not with pressure-rate product at maximum exercise (MaxPRP). The variables most correlated with Ext, RestPRP and MaxPRP were the indicators of diltiazem sensitivities calculated from the relationships between effects and plasma diltiazem concentration. An elimination rate constant (K_e) was found to affect indicators of diltiazem sensitivity during exercise, suggesting that the effects of diltiazem during exercise depend on the tissue distribution of diltiazem. The reproducibility of the predictive models derived from the multiple regression analysis was satisfactory, suggesting that these models may be useful in predicting the effects of diltiazem in individual cases by analyzing plasma diltiazem concentration data.

View full abstract

It is known that glucagon is a peptide hormone consisting of 29 amino acids and regulates glycometabolism by acting in coordination with insulin. However, there are not many reports regarding its pharmacokinetics. The glucagon described in these reports are of animal pancreatic origin, but a glucagon by utilization of genetical engineering technique by the use of yeast fungus has been developed recently.
We have made an assessment this time regarding the safety and pharmacokinetics in man of the glucagon (GL-G) by genetical engineering by administering it subcutaneously and intravenously in a single dose (1mg) each to ten Japanese healthy volunteers as subjects (age 20-25, average 22).
The results were as follows:
1) No subjective symptom, abnormal clinical laboratory value or abnormal physiological test result ascribable to GL-G administration or found problematic in the clinical aspect was observed.
2) The findings obtained regarding the blood glucagon concentration (IRG) by subcutaneous administration were: T_max-8.0±1.1min(mean±SE); C_max-6, 629±476pg/ml; AUC-4, 710±301pg·hr/ml; and T_1/2-19.9±1.5min. The findings by intravenous administration turned out to be T_1/2-3.1±0.2min and AUC-6, 394±937pg·hr/ml, the latter being about 1.4 times as large as that by subcutaneous administration.
3) The in vivo pharmacokinetics of BS, IRI, CPR and GH agreed well with the glucagon of animal pancreatic origin, from which it was assumed that the glucagon has the same physiological activity.
From the above, it has been concluded that GL-G poses no problem regarding its safety within the range of the dosage used in present test and is a preparation with the possibility of clinical application in future.

View full abstract

The relationships between serum glycoside concentrations, which were obtained from patients during maintenance therapy with digoxin (D3) or β-methyldigoxin (β-MD), and patient factors (age, sex, body weight and renal function) were investigated. Serum concentrations were measured by fluorescence polarization immunoassay with TDx digoxin assay kit (Dainabot). From February 1983 to July 1987, a total of 729 serum samples was received by our laboratory for therapeutic drug monitoring of D3 and β-MD and 182 of these samples were used for this study (D3-treated group, n=50; β-MD-treated group, n=132). For the patients with normal renal function (serum creatinine level≤1.3mg/dl) in each group, no significant differences of mean serum glycoside concentrations were observed between male and female, and none were also observed between patients aged over 60yr and ones aged under 60yr. Each serum glycoside concentration was correlated significantly with dose/kg of body weight [D3, r=0.412 (P<0.01); β-MD, r=0.415 (P<0.001)] and also with creatinine clearance [0.25mg D3, r=0.463 (P<0.01); 0.1mg β-MD, r=0.658 (P<0.001)]. When the serum glycoside concentrations were compared between the D3-treated group and the β-MD-treated group, the dosage ratio (β-MD/D3) to obtain the same serum concentrations was 0.6. However, over 60% of patients were given 0.25mg D3- or 0.1mg β-MD as daily dose and its dosage ratio was 1:0.4 (D3-: β-MD). On comparing the distribution of serum glycoside concentrations between both groups during maintenance therapy, the serum concentrations of the β-MD-treated group were found to be lower than those of the D3-treated group (Kolmogorov-Smirnov test: P<0.005).

View full abstract

The interindividual relationship between unbound fraction of valproic acid and some factors such as total drug concentration, level of albumin, free fatty acids (FFA) and total bilirubin was investigated after repeated oral doses in 7 healthy adults. All serum samples (n=63) were collected just prior to the last dose and the following times there-after.
The correlation between unbound fraction and both corresponding each variable value and ratio of FFA/albumin and total bilirubin/albumin was determined in all samples (method (1)). Secondly, the correlation between individual average unbound fraction and both average values for each variable and ratio of FFA/albumin and total bilirubin/albumin of individual was also determined (method (2)).
For applied method (1), there was significant positive correlation between unbound fraction and both total drug concentration (P<0.001) and FFA/albumin ratio (P<0.01). On the other hand, for applied method (2), there was significant positive correlation only between average unbound fraction and average value for total drug concentration (P<0.001).
In the evaluation on these results by using in vivo binding parameters (K for association constant, and (P) for concentration of free protein) of the Scatchard plot, we observed the specific binding characteristics between valproic acid and serum albumin within the investigated range of total concentration (<420μmol/l). Additionally, we showed that the mechanism of altered binding characteristics depended onn both changes in K (P) affected by average total concentration and K by average FFA/albumin ratio.

View full abstract

To evaluate the effect of metoprolol, a β₁-selective adrenoreceptor blocking agent, on the circadian rhythms of blood pressure (BP) and heart rate (HR), ambulatory BP and HR monitoring was performed in subjects with essential hypertention before and 4wk after the treatment. BP and HR were measured with ABPM-630 (Colin, Japan) every 30min for 48hr, and were analyzed by conventional statistic method, cosinor method and Fourier transformation.
The circadian patterns of systolic BP and diastolic BP were not affected by metoprolol while its antihypertensive effect was confirmed.
However, the circadian rhythm of HR was significantly depressed by metoprolol. It was suggested that the circadian rhythm of BP would be preserved through the modulatory role of HR after metoprolol.
These findings indicate the importance of the individualization of effects of antihypertensive agents on the circadian rhythms of BP and HR.

View full abstract

We prepared three kinds of morphine suppositories: HE was based on the equivalent mixture of Witepsol H-15 and E-75; S was based on Witepsol S-55 alone; MSC contained controlled-release morphine tablet (MS Contin) in the same base as HE. The pharmacokinetics after rectal administration of the preparations was investigated in rabbits. We found that HE had short T_max (10min) and that the sustained release continued around 6hr after administration. The extent of bioavailability (BA) of HE was 43.4%, and the plasma concentration of morphine was higher than orally administered MS Contin tablet, throughout the observation period. S had a high BA (95.1%) but C_max (446.2ng/ml) was too high judged from some risk of adverse effect or dependence. Thus we considered it is not appropriate for clinical use. On the other hand, MSC had longer T_max (150min). The plasma concentration 12hr after administration was around half the C_max and the sustained release was found to be good. The MSC's BA also showed high value and only a little dispersion (78.3±6.6%). The cumulative absorption-time profiles of MSC in vivo approximated to the morphine-release behavior of MS Contin tablets in vitro.
From the facts described above we conclude:
1. We can expect the same or more analgesic effect from HE than oral MS Contin tablets.
2. MSC is a good sustained-release morphine suppository which can be expected to be useful for cancer pain therapy, through every 12-hr administration.

View full abstract

A total of 237 healthy male volunteers took drugs for phase I trials. Serum transaminase values (GOT and GPT) were maintained within normal ranges in most of them. However, GOT or GPT was elevated to an abnormal level in 9.3% of them after the administration.
After investigating the clinical features of the “transaminase-elevated group” and the “non-elevated group”, we concluded that GOT or GPT is likely to be elevated in subjects with GOT<GPT, high obesity index, high serum γ-glutamyl transpeptidase, or a combination of any of the three. These subjects should be excluded from phase I trials for an accurate evaluation of the safety of a drug.

View full abstract

The tolerability and kinetics of a new cerebral function activator, oxiracetam (CT-848), after single oral administration (dose: 400, 800, 1, 600 and 3, 200mg) was investigated in 8 healthy Japanese volunteers (active drug, 6; placebo, 2).
At the same time, the effect of food on the kinetics of oxiracetam was investigated after single dosing (800mg) in the same volunteers.
As subjective symptoms, sleepiness and heaviness in the head were observed after active drug and placebo administration, but were slight and transient. Clinical laboratory test values and vital signs were not notably changed with oxiracetam administration.
Peak plasma levels were reached within approximately 1hr (T_max) after administration of 400, 800, 1, 600 and 3, 200mg (C_max): 11.89, 18.82, 43.11 and 72.64μg/ml, respectively, and the biological half-life of the β-phase was 5.7-9.8hr under fasting conditions. The average recovery (0-48hr) in urine was 57-77% after dosing.
While the T_max of oxiracetam was significantly altered in fasting volunteers and in volunteers after a meal, AUC, C_max and urinary excretion were not significantly changed.
The above results confirm the safety of oxiracetam given as a single oral administration to healthy Japanese volunteers.

View full abstract

A new cerebral function activator, oxiracetam (CT-848), was given orally by multiple t. i. d. administrations of 800mg to 8 healthy Japanese volunteers for 8 days (active drug, 6; placebo, 2), and its tolerability and pharmacokinetics studied.
As subjective symptoms, constipation and heaviness in the head were observed after administration, but were slight and transient.
Clinical laboratory test values and vital signs were not notably changed with oxiracetam administration.
The unchanged plasma concentration reached a constant level on the 2nd day. Plasma level elimination patterns after final administration was practically the same as after single administration.
There was no significant difference in the cumulative amounts of urinary excretion over 24hr when measured from the first to the 7th days of drug administration.
Accumulation of the drug was not observed with multiple administration, and oxiracetam had a good tolerability profile in healthy volunteers.

View full abstract

On Nov. 9, 1988, the Ministry of Health and Welfare (MHW) published the draft for Good Post-Marketing Surveillance Practice (GPMSP: standard for implementation of the post marketing surveillance (PMS) for the reexamination application of new drug) based on the investigation on the pharmaceutical companies' PMS practice for the reexamination application of new drugs in Jul. 1988. During a period from Dec. 1989 to Jan. 1990 the MHW repeated investigation on the PMS practice of pharmaceutical companies in order to know the extent to which pharmaceutical companies met the requirements provided by the draft GPMSP.
This report explains and analyzes the result of present investigation and compares them with those of the previous investigation. Both investigations were conducted by sending questionnaire in advance to pharmaceutical companies (130 at this investigation and 127 at previous one) that hold approvals of new drugs which are subject to the reexamination, or to those who are entrusted the PMS for the reexamination by the pharmaceutical companies. Interviews with the persons in charge of the PMS for the reexamination were performed using questionnaire by MHW.
The extent to which pharmaceutical companies met the requirements provided in the draft GPMSP was generally increased and in several items the extent was significantly increased. The public announcement of the draft might bring about these improvements.

View full abstract

[in Japanese]

View full abstract