Mitsutaka Kanamaru

Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects

SummaryThe uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n=6), or 100 mg (n=6) or placebo (n=3) once daily for 7 consecutive days.In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg dl−1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged.In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg·dl−1) and last administrations (4.42 mg·dl−1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576).The findings suggest that DuP-753 posesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.

The pharmacokinetics of the β2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation

SummaryWe have studied the pharmacokinetics of tulobuterol given transdermally or by aerosol inhalation in healthy male volunteers.Tulobuterol was rapidly absorbed after inhalation, with a tmax of 0.8–1.5 h. The Cmax and the AUC increased linearly with dose.Tulobuterol was well absorbed after transdermal administration, with an absorption lag-time of about 4 h. The Cmax and AUC increased linearly with dose and the tmax was about 9–12 h. The mean percentage of drug absorbed during the application of a patch for 24 h was 82–90% after a single dose and 82–85% during repeated dosing.The mean urinary recoveries as unchanged drug after a single inhalation and patch application were 3–4% and 5–6% respectively.Tulobuterol did not accumulate during repeated inhalation or transdermal application. It was well tolerated, except for an increase in heart rate of 10–20 beats · min−1 after five repeated applications of a 4 mg patch.

Dihydropyrimidine Dehydrogenase Activity in 150 Healthy Japanese Volunteers and Identification of Novel Mutations

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme catalyzing the metabolic degradation of the anticancer drug 5-fluorouracil (5-FU). Population studies of DPD activity in peripheral blood mononuclear cells (PBMC) were reported in healthy volunteers and cancer patients. Although these studies were done in mainly Caucasian and African American populations, only a little information is available for a Japanese population. Experimental Design: One hundred fifty healthy Japanese volunteers were screened for a population distribution of PBMC-DPD activity. Genetic analysis of a volunteer with very low DPD activity was carried out by reverse transcriptase-PCR and genomic sequencing. Bacterially expressed recombinant mutant DPD proteins were purified and characterized. Results: Mean and median values of PBMC-DPD activity for 5-FU reduction in the study population were 0.173 and 0.166 nmol/min/mg protein, respectively. A 57-year-old female volunteer (proband in this study) had very low DPD activity (0.014 nmol/min/mg protein) with a very low level of expression of DPD protein. Two novel nucleotide substitutions, at nucleotide positions 1097 (1097G > C) and 2303 (2303C > A), resulting in amino acid substitutions at positions 366 (G366A) and 768 (T768K), respectively, were identified. The G366A mutation caused not only a marked decrease in the affinity of the enzyme to cofactor NADPH but also reduced Vmax for 5-FU-reducing activity to ∼0.5. T768K mutant lost its activity much faster than did wild DPD. Conclusions: We found one healthy volunteer (0.7% of the population) with very low PBMC-DPD activity due to heterozygosity for a mutant allele of the DPYD gene in a population of 150 Japanese.

Pharmacokinetics and Safety of a Novel Recombinant Soluble Human Thrombomodulin, ART-123, in Healthy Male Volunteers

The safety and pharmacokinetics of a novel recombinant soluble human thrombomodulin, ART‐123 were evaluated in single‐ and multiple‐dose studies involving 16 healthy male volunteers. ART‐123 was administered by intravenous infusion over 2 hours. The single‐dose study indicated that plasma ART‐123 levels at doses of 0.03, 0.1, and 0.3 mg declined biexponentially and those half‐lives were approximately 4 hours (t1/2α) and 20 hours (t1/2β), respectively. The mean plasma peak concentration and area under the plasma concentration—time curves increased in proportion to the given doses. Mean urinary recovery within the first 48 hours was between 54.3% and 59.8% of dose. In the multiple‐dose study, ART‐123 was administered at a dose of 0.2 mg once daily for 3 days. ART‐123 did not accumulate as judged from plasma concentrations and urinary recovery. There were no abnormal findings in objective symptoms and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, bleeding time, coagulation and hemostatic parameters, blood chemistry, and urinalysis. There were no significant adverse reactions or abnormalities in physical and laboratory examinations that could definitely be attributed to the drug at a dose of 0.3 mg as a single administration and at a dose of 0.2 mg once daily for 3 days. These results indicate that ART‐123 is safe at doses up to 0.2 mg once daily for 3 days and may have clinical application. Further studies are needed, however, to evaluate the safety and pharmacokinetics of ART‐123 in the targeted population.

Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers

Abstract— The pharmacokinetic and pharmacodynamic properties of (+)‐sotalol (BMY‐5763) were studied to analyse the relationship between plasma concentration and QTc prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6·5 days, and single intravenous doses of 1·0 and 1·5 mg kg−1. The plasma concentration of (+)‐sotalol peaked about 3 h after oral administration and declined with a half‐life of 7·9–9·7 h. The Cmax and AUC showed dose‐related increases, while the urinary recovery as the unchanged form remained constant (66–68% of the dose). During repeated oral administration the plasma concentration of (+)‐sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)‐sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)‐sotalol in plasma decreased biexponentially with a terminal half‐life of 7·6–8·3 h and the urinary recovery as unchanged drug amounted to 84–88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QTc interval and concentration of (+)‐sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)‐sotalol, a combined pharmacokinetic‐pharmacodynamic model was attempted by assuming an effect compartment. This analysis was shown to be effective to adjust the lag of effect behind a rapid change in plasma concentration which occurred in the early distributive phase because there was no evidence that the metabolite made any significant contribution to the effect of (+)‐sotalol.

Phase I Study of Y-20811, a New Long-Acting Thromboxane Synthetase Inhibitor by Intravenous Administration

The safety, pharmacological action and pharmacokinetics of Y‐20811, a thromboxane (TX) synthetase inhibitor, were investigated by single intravenous administration of 5, 10, and 25 mg each to six healthy adult male volunteers.

Phase I study of cefixime, a new oral cephalosporin

The tolerance to and pharmacokinetics of cefixime, a new oral cephalosporin, were evaluated in healthy volunteers given the drug in single doses of 50, 100, and 200 mg and repeated doses of 200 mg bid for 14 days. In the repeated‐dose study, there were mild and transient subjective symptoms such as soft stools, diarrhea, and anorexia, which disappeared without additional treatment during the dosing period. Slight increases in eosinophil and serum amylase levels were also observed. The serum concentrations of cefixime peaked at 0.71, 1.17, and 2.08 μg/mL on average, four to five hours after dosing with 50, 100, and 200 mg, respectively, and the half‐lives were 2.54, 2.38, and 2.29 hours. Serum concentrations and urinary recoveries after dosing with 100 mg were little affected by food ingestion. There was no evidence of cefixime accumulation in the body by repeated dosing since mean serum concentrations and urinary recoveries were almost the same on the first, third, seventh, and 14th days of dosing.

Pharmacokinetic and Pharmacodynamic Properties of a New Thromboxane Receptor Antagonist (Z‐335) after Single and Multiple Oral Administrations to Healthy Volunteers

The pharmacokinetics and pharmacodynamics of a new oral thromboxane (TX) A2 receptor antagonist, Z‐335, were studied in healthy male volunteers following single doses (0.5–40 mg, PO) in a dose‐escalating manner and multiple doses (40 mg, PO, once daily for 7 consecutive days) with a single‐blind, placebo‐controlled design. Serial blood and urine samples were analyzed for Z‐335 and its metabolites to obtain key pharmacokinetic parameters. In the single‐dose (10, 20, and 40 mg) study, the maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) increased in proportion to the dose when administered after fasting, while the mean elimination half‐life (t1/2β) was essentially unchanged (7.79‐7.93 h). Recovery of the unchanged and taurine‐conjugated drugs in the urine within 24 hours was 6.5% to 8.4% and 11.9% to 14.2%, respectively. These parameters essentially remained unchanged when the effect of meal intake was evaluated at the dose of 20 mg with a crossover design. Ex vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was completely inhibited within 2 hours after all doses, and complete inhibition was maintained for 12 to 14 hours, depending on the dose. The aggregation induced by collagen was also inhibited to a lesser extent, whereas that by adenosine diphosphate was hardly influenced. In themultiple‐dose study, Cmax and AUC0–24 were increased by 34% after the last dose compared with the first dose. Z‐335 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, which returned, however, almost to the control level 48 hours after the last dose. The agent was well tolerated without any abnormalities in subjective and objective symptoms, blood biochemistry, hematology, and urinalysis definitely attributable to the agent, except for the changes expected from its TXA2 receptor‐antagonizing actions. Z‐335 was concluded to be safe and to provide long‐lasting blockade of TXA2 receptors on the basis of a once‐daily regimen, promoting further clinical evaluation.

Aldose reductase inhibitory and uricosuric activities of FK366 in healthy volunteers.

The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependency, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half‐life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.

Usefulness of grading of neutrophil aggregate size by laser-light scattering technique for characterizing stimulatory and inhibitory effects of agents on aggregation.

We attempted to apply the particle counting method that employs laser-light scattering technique to quantify the change in numbers of neutrophil homotypic aggregates of 3 graded-sizes (small, medium and large). Ex vivo activation of human neutrophils by a chemotactic peptide, fMLP, predominantly produced small-sized aggregates (< 15 cells), and also, transiently, medium-sized aggregates (16-130 cells). Co-treatment of neutrophils with fMLP and cytochalasin B mainly produced medium-sized aggregates, with very few large-sized aggregates (> 130 cells). Interestingly, when protein kinase C was activated with phorbol 12-myristate 13-acetate small-, medium- and even large-sized aggregates of neutrophils were formed. Presence of extracellular calcium was required to produce these neutrophil aggregations. Both prostaglandin E2 (PGE2) and wortmannin, an inhibitor of phosphatidyl inositol 3-kinase (PI-3K), inhibited neutrophil aggregation, whereas dbcAMP, a cell permeable analog of cyclic AMP, did not, confirming that PGE2 causes neutrophil aggregation probably through PI-3K inhibition rather than activation of adenylate cyclase. These results suggest that the application of the light scattering technique to characterize human neutrophil aggregates by both size and numbers, has advantages over conventional optical turbulent aggregometry, in that it discriminates neutrophil aggregations produced by different mechanisms of intracellular signaling.