Healthy Japanese Volunteers Research Articles

Pharmacokinetics and safety of azthreonam in healthy Japanese volunteers.

Azthreonam (SQ26, 776), a new, completely synthetic, monocyclic β-lactam antimicrobial agent, was administered to 29 healthy, Japanese male volunteers by intravenous bolus infusion, intravenous drip infusion, and intramuscular injection as single doses, and intravenous bolus infusion as multiple dose. The pharmacokinetics of single intravenous doses of 500 mg, 1000 mg and 2000 mg were best described by a linear open two-compartment model. The mean peak serum levels were proportional to the doses but the mean serum half-life was essentially independent of the dose administered (t1/2=1.5-1.8h).The urinary excretion within 24h ranged from 60-70% of the dose administered as intact azthreonam. Usually, intravenous doses were primarily excreted in the 8h urine. The pharmacokinetics of an intramuscular dose of 1000 mg fitted a linear open one compartment model with a mean peak serum level of 66μg/ml at 1h after dosing, and the urinary excretion rate was 80% of the dose administered within 24h. In the multiple dose regimen with 1000 mg of azthreonam administered intravenously to six healthy male subjects every 12h for 5 days, the mean peak serum levels and urinary excretions did not suggest any evidence of drug accumulation. The results of physical examinations and laboratory tests indicated azthreonam was well tolerated with only moderate reversible elevation of CPK values in all subjects at 24h after intramuscular administration.

健常人における徐放性Ａｓｐｉｒｉｎ製剤の薬物動態 脂溶性Ａｓｐｉｒｉｎか粒と徐放性Ａｓｐｉｒｉｎ錠の比較

Acetylsalicylic acid (ASA) and salicylic acid (SA) concentrations in plasma were determined by high-pressure liquid chromatography in 14 healthy male Japanese volunteers after single oral administrations of two different aspirin formulations, enteric-coated granules (Minimax®) and a slow-release tablet (Verin®). Seven subjects received 650 mg and the other seven subjects received 1300 mg of each formulation in a randomly assigned cross-over study. Mean peak SA concentrations in the plasma were significantly higher with the enteric-coated granules than with the slow-release tablets (P<0.001 with both 650 mg and 1300 mg doses), although the times to peak SA concentration in the plasma were not different between the two formulations. Plasma ASA concentrations were detected only following administration of the enteric-coated granules. Mean elimination half-lives (t1/2) of plasma SA were significantly longer with the slow-release tablets at both doses (P<0.05 at 650 mg and P<0.01 at 1300 mg) and the mean areas under the curves (AUC∞0) were significatly greater with the enteric-coated granules at both doses (P<0.001 at 650 mg and P<0.05 at 1300 mg). Racial differences in SA kinetics between the Japanese and the American subjects were suggested by the results of the study.

Ｃｉｓａｐｒｉｄｅの臨床第１相試験 ＩＩ 反復経口投与試験

A Phase I study on cisapride (R 51 619), a new gastrointestinal prokinetic agent, was conducted in 12 healthy Japanese male volunteers. The safety and pharmacokinetics of the drug were studied in repeated oral doses of 15 mg/day and 30 mg/day.The volunteers were randomly divided into two groups (group 1 and group 2). The six men of group 1 received 15 mg/day t.i.d. for 5 days and the remaining six individuals (group 2) were given 30 mg/day t.i.d. for 7 days.No abnormalities were observed in the vital signs, ECGs or laboratory tests. Among subjective symptoms, one individual in each group complained of a slight feeling of heavyheadedness and headache on the first day of administration.The measured plasma levels of unchanged cisapride in this study almost coincided with the simulation curves which were defined based on the parameters obtained in the single oral dosing study. Moreover, the plasma levels reached steady states on the 3 rd or 4 th day of administration.The serum levels of prolactin rose temporarily within the normal range on the first day of administration and normalized after repeated dosing.The above results confirmed the safety of cisapride in repeated oral dosing in healthy male volunteers.

Alcohol and the Heart

To evaluate the hemodynamic changes related to alcohol flush, the effects of ethanol intake (0.5 g/kg) were studied by echocardiography and systolic time intervals in 10 Finnish and 9 Japanese healthy volunteers. In 5 Japanese subjects, post-drink facial flush was associated with elevated blood acetaldehyde (peak levels 20-83 mumol/l) and marked cardiocirculatory stimulation. Heart rate was increased directly post ingestion by 65% (p less than 0.01), stroke index by 23% (p less than 0.05), and cardiac index by 106% (p less than 0.05). Diastolic blood pressure was simultaneously decreased by 23% (p less than 0.05), peripheral vascular resistance by 54% (p less than 0.01), and circumferential wall stress by 22% (p less than 0.05); ejection fraction was raised by 26% (p less than 0.01). The other Japanese and the Finnish subjects had no detectable acetaldehyde in blood after ethanol ingestion. The average hemodynamic alterations in them were similar in direction to the changes presented above, but quantitatively 6-10 times smaller (p less than 0.005 for each of these variables). Thus, in Orientals with genetically defective acetaldehyde oxidation, ingestion of even small amounts of alcohol evokes intense enhancement of left ventricular function, probably because of acetaldehyde-induced catecholamine release and peripheral vasodilation.

Ｂｒｏｔｉｚｏｌａｍ（ＷＥ９４１）の臨床薬理学的検討 第一相試験

A phase I study of brotizolam has been performed with 9 healthy male Japanese volunteers. After a single oral administration of 0.125 mg, 0.25 mg and 0.5 mg in 3 volunteers respectively, psychic and physical symptoms, vital signs, ECG, laboratory values (urine, blood and blood chemistry tests) and blood levels were examined.1. Induction of sleep due to the action of the drug and decrease in blood pressure due to the induced sleep were observed dose-dependently. A tendency of decrease in respiratory rate was also noted, but it was not a clinically meaningful change. A peak of these effects appeared around 2 hrs after administration and thereafter disappeared gradually in approximate conformity with the change of plasma concentration of brotizolam.2 . The secondary effects such as unsteadiness, dizziness and dullness, and other symptoms, e. g. dry mouth, were observed, but these symptoms were mild and appearedto have no clinical significance.3. No abnormal laboratory findings were noted.4 . Plasma concentration of brotizolam reached its maximum at 0.5-4 hours after oral administration. Almost linear correlation was found in the relations between Cmax and administration doses, and between AUC and administration doses.The above results establish the safety of brotizolam in healthy Japanese volunteers.

Ｍｉｄａｚｏｌａｍの臨床薬理学的検討 第１相試験

We carried out a Phase I Study of midazolam in healthy Japanese male volunteers and studied the safety of the drug in different 3 doses (0.1, 0.2, 0.3 mg/kg) administered intravenously and 1 dose (0.2mg/kg) intramuscularly.No remarkable change was seen in either psychosomatic symptoms, vital signs or laboratory tests.Sedation was observed characteristically in almost every case. Respiratory depression in dose-independent manner was observed in 0.3 mg/kg administered intravenously. Plasma half-life of midazolam, 1.82-2.68 hr, is far shorter than that of diazepam.The above results confirmed the safety of midazolam in healthy male Japanese volunteers.Therefore, we conclude that we can proceed to a Phase II Study with this drug.

Biotyping of Propionibacterium acnes isolated from normal human facial skin.

Biochemical and serological characteristics of 128 strains of Propionibacterium acnes isolated from the facial skin of healthy Japanese volunteers were compared with the three standard strains of the American Type Culture Collection, ATCC 6919, 11827, and 11828. Accordingly, the isolated strains of P. acnes were classified into five biotypes (B1 to B5) on the basis of fermentation tests of ribose, erythritol, and sorbitol. Two serotypes were distinguished by the agglutination test. P. acnes belonging to serotype I had galactose as a cell wall sugar, whereas those of serotype II lacked galactose. The strains of serotype I were distributed among all five biotypes (B1 to B5); however, those of serotype II consisted only of one biotype (B2). A term "sero-biotype" was introduced to differentiate and carefully classify the isolates. The predominant sero-biotypes differed with the individual and region of the facial skin. In general, strains of sero-biotype IB1, IB3, IB4, and IIB2 were more frequently isolated than those of sero-biotype IB2 and IB5. Thus, for routine assay work, serotyping of P. acnes as based on erythritol and sorbitol fermentation is both practical and applicable.

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Relations between the HLA-antigens and immune responsiveness to SK/SD in healthy Japanese subjects.

A possible association between the HLA antigens and immune responsiveness to SK/SD was studied in 90 healthy Japanese volunteers. No association was found between the HLA antigens, including B5, and SK/SD stimulated blastoid transformation. There was a week indication of an association between Bw22 and responses to SK/SD. But this was not statistically significant as far as the corrected P value was concerned.

Effects of a New Anti-inflammatory, Analgesic and Antipyretic Drug MK-647 (Diflunisal) on Healthy Japanese Volunteers

A new anti-inflammatory, analgesic and antipyretic drug MK-647 was given orally in varying doses to a total of thirteen healthy Japanese volunteers for the observation of its influence on the findings of their physiological functions, heamtological tests, urinary analysis and sero-biochemical tests. At the same times, surveys were made on the changes produced in its blood level, urinary excretion and analgesic effects.As the result, no abnormality was observed on the physiological functions except an increase in the bowel sound provided the dosage employed was below 500mg at a time. This enhancement of the bowel sound, however, indicates a possibility for the development of gastrointestinal side effects.As for laboratory tests, an increase in alkaline phophatase was observed. A care should be taken on this matter when carrying out clinical studies in the future.Accumulation may be negated in view of the change in its blood level, however. Compared with acetylsalicylic acid, its effect was rather delayed in onset and lasted longer. Satisfactory clinical effect may be expected with administration twice a day.