A newly synthesized ketone oxime derivertive, 2, 3-dichloro-4-methoxyphenyl 2-furyl ketone (E)-0- [2-(diethylamino) ethyl] oxime (ANP 4364), was administered orally to 6 healthy volunteers to investigate its safety, pharmacodynamics, and pharmacokinetics.
Six volunteers received single oral doses of 50, 100, 200 mg, and 3 consecutive doses of 100 mg, of ANP 4364.
ANP 4364 caused slight hypotension, with a transient tachycardia, and a tendency towards increasing stroke volume revealed by impedance cardiography.
No findings attributable to the drug were observed in the ECG or body temperature records.
Pharmacokinetic analysis revealed that unchanged ANP 4364 was rapidly absorbed with a mean half-life of about 10 hours. After administration of 100 mg, 0.16% of the dose of ANP 4364 was excreted in urine within 24 hours. Subjective symptoms possibly produced by the drug were headache, a heavy feeling of the head, a feeling of warmth in the face, and numbness of the tongue ; there was one subject, however, who complained of nausea.
Examination of the blood and urine showed no abnormal findings attributable to administration of the drug.
In conclusion, it was found that ANP 4364 seems to have vasodilating action and is well-tolerated in man.

View full abstract

A sustained-release dosage form of isosorbide dinitrate (Frandol^®) has been developed for the purpose of prolonging the preventive effect of isosorbide dinitrate (ISDN) against attacks of angina pectoris.
According to the JP IX disintegration test (with slight modification), the dissolution rate of Frandol was slow, with a 50% dissolution time of about 3 hr on the other hand, disintegration of the standard tablet (Nitorol^®) was very rapid, almost entirely dissolving within 10 min.
After administration of Frandol (20 mg) to six healthy volunteers, the plasma level of ISDN slowly increased to the maximum level at 3 hr and remained at a high level for 6 to 8 hr. However, after administration of the standard tablet (5 mg), the plasma level of ISDN rapidly increased to the maximum level within 30 min, but thereafter decreased rapidly.
According to the pharmacokinetic analysis based on a two-compartment open model, the bioavailability of ISDN after dosing of the standerd tablet was about 7%, while the bioavailability of Frandol relative to the standard tablet was 95%.
Computer-simulated pharmacokinetic data at the steady-states by repeated administrations of the standard tablet (8 hr interval) and Frandol (12 hr interval) were as follows: the average plasma concentrations of ISDN with the standard tablet and Frandol were 0.93 and 2.56 ng/ml, respectively ; and the minimum plasma concentrations with the standard tablet and Frandol were 0.11 and 1.40 ng/ ml, respectively ; and the maximum plasma concentrations with the standard tablet and Frandol were 5.32 and 3.52 ng/ml, respectively.
These results indicated that Frandol may be an ideal sustained-release dosage form of ISDN for the prevention of angina pectoris, since the plasma ISDN level is maintained at a high level constantly without the production of an excessively high plasma level.

View full abstract

The biological fate of suxibuzone (SB), a new non-steroidal anti-inflammatory agent, was studied in healthy male volunteers with single oral doses and compared with that of phenylbutazone (PB) by a cross-over test, with the following results:
1) PB, oxyphenbutazone (Oxy-PB), and γ-hydroxy-phenylbutazone (γ-Hydroxy-PB) were identified in plasma after oral administration of SB. Moreover these metabolites, their glucuronides, SB-glucuronide, 4-hydroxymethyl-phenylbutazone (4-HM-PB)-glucuronide, and p, γ-dihydroxy-phenylbutazone (p, γ-DH-PB) were found in urine.
2) Peak plasma concentration of the metabolites was obtained 4 hrs after a single oral dose of 426 mg of SB when the concentration of PB, the main metaboliteof SB, was 36μg/ml, much the same as the corresponding level in the volunteers receiving PB. On the other hand, there was no difference between volunteers receiving SB and PB interms of the concentration of Oxy-PB. But the concentration of γ-Hydroxy-PB was higher after oral SB than after oral PB.
3) Urinary excretion of the metabolites was about 8% of the administered dose up to 16 8hrs after oral doses of SB or PB, but in the period shortly after oral doses of SB, Oxy-PB-glucuronide and γ-Hydroxy-PB were excreted to ag reater extent than after oral doses of PB.
4) From these results in the plasma and urine after oral doses of SB, it was found that SB may be characterized as a prodrug of PB.
5) During the experiment, no side effects or abnormalities were observed in the medical examination and laboratory test except for a slight decrease in the uric acid level in plasma.

View full abstract

The following study was conducted to examine the absorbability of beclomethasone dipropionate when inhaled through the nose or nose and mouth. Blood and urine samples were obtained from 10 normal, healthy volunteers both before and after either nasal inhalation of beclomethasone dipropionate (Aldecin Nasal) at doses of 800μg/day for 4 weeks or simultaneous nasal inhalation at doses of 400 μg/day with oral inhalation (Aldecin Inhaler) at doses of 400μg/day for 4 weeks. The serum and urine concentrations of immunoreactive-beclomethasone were determined by the radioimmunoassay method in which anti beclomethasone-21-BSA serum was used. In addition, the serum total corticoids level was determined with Murphy's competitive protein binding assay for comparison with the serum immunoreactive-beclomethasone levels.
As a result, the serum immunoreactive-beclomethasone levels after the administration period were found not to differ from the levels obtained in the preadministration period, and were also comparable with the total corticoids levels. The urine immunoreactive-beclomethasone levels after the administration period also did not change much from the preadministration levels, and were nearly comparable to the known total corticoids levels for normal subjects. These results indicate that absorption of beclomethasone dipropionate when inhaled through the nose or mouth is almost nil.

View full abstract

An automatic continuous systolic blood pressure monitor (Shimazu SCS-501) and a deep body thermometer (Terumo finer core temp DC-1) were used to observe hemodynamic changes induced by thymoxamine hydrochloride, FK 749, and hemodialysis. Three actue hypotension cases were observed in these studies.
By means of SCS-501, DC-1, and a sphygmomanometer, it was suggested that the acute hypotension cases differed from each other. From these observations the authors concluded that the combined use of SCS-501 and DC-1 with an ordinary sphygmomanometer gives them detailed information about hemodynamic changes and that both pieces of equipment will be very useful in estimating the safety and effects of drugs.

View full abstract