Pharmacokinetic and Pharmacodynamic Properties of FK070 (KDI-792), A Novel Thromboxane Receptor Antagonist/Thromboxane Synthetase Inhibitor,After Single and Multiple Oral Administrations to Healthy Volunteers

FK070, a thromboxane A₂ (TXA₂) receptor antagonist/TXA₂ synthetase inhibitor, was given orally to healthy male volunteers in a single-and multiple-dose study. In the single-dose study (200, 300, 400 mg), the area under the plasma concentration—time curve (AUC) and the maximum plasma concentration (C_max) increased non-linearly with dose, while the mean elimination half-life (t¹_β) was essentially unchanged (3.9-7.3 h). Recovery of the unchanged drug in the urine was 12–25%. C_max and AUC as determined with 200 mg of drug after a meal decreased by about 60 and 30%, respectively. Ex-vivo platelet aggregation in the plasma by a TXA₂ analogue, U46619, was almost completely inhibited within 1 h, after all doses of drug, with a significant dose-dependent inhibition maintained for 8 h or more, which was much longer than was expected from drug plasma concentration. The aggregation by adenosine diphosphate (ADP) was inhibited to a lesser extent. FK070 also inhibited TXA₂ synthetase as evidenced by decreased production of TXB₂ and reciprocally increased production of 6-keto-prostaglandin F_1α in the serum during ex-vivo whole blood coagulation. These effects peaked 1 h after drug and lasted until 4 h with the higher doses. In the multiple-dose study (300 mg, twice a day, after meals for 6.5 days), drug concentrations in the plasma were well fitted to a three-compartment open model with first-order absorption. FK070 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, with a significant inhibition lasting as long as 48 h after conclusion of administration. No clearly drug-related changes were found in routine laboratory tests, subjective and objective findings, or vital signs. FK070 was concluded to be well tolerated and to provide long-lasting blockade of TXA₂ receptors, and plasma concentration-dependent inhibition of TXA₂ synthetase in the platelets.     

Pharmacokinetics and pharmacodynamics of ()-sotalol in healthy male volunteers

1 We investigated the pharmacokinetics and pharmacodynamics of (±)-sotalol administered orally to healthy male volunteers in single doses of 40, 80 and 160 mg and in multiple doses of 80 mg twice daily for 7 consecutive days.
2 In the single dose studies, the half-life of (-)-sotalol (7.2-8.5 h) was significantly ( P < 0.01) shorter than that of (+)-sotalol (9.1-11.4 h) while the renal clearance of (-)-sotalol (110.6-126.4 ml min^-1) was significantly ( P < 0.01) faster than that of (+)-sotalol (102.2-110.1 ml min^-1). In the multiple dose studies, similar differences in the pharmacokinetics of (+)- and (-)-sotalol were observed. In addition, the pharmacokinetics of both (+)- and (-)-sotalol on day 4 were shown to be essentially the same as those on day 7.
3 In pharmacodynamic examinations, (±)-sotalol prolonged QTc intervals on electrocardiograms dose-dependently after single doses of 80 and 160 mg (3.81 ± 2.96%, 13.23 ± 5.66%). The correlation between the plasma concentration of (±)-sotalol and prolongation of QTc intervals was nearly linear, and showed no hysteresis.
4 In conclusion, we demonstrated that QTc interval was prolonged with a linear correlation to the plasma concentration of (±)-sotalol. In addition, our study suggested that differences in the pharmacokinetics of (+)- and (-)-sotalol may be attributable to faster urinary excretion of (-)-sotalol.     

Prediction of Optimal Atrioventricular Delay in Patients with Implanted DDD Pacemakers

In patients with an implanted DDD pacemaker (PM), the atrial contribution may be interrupted by too short an atrioventricular (AV) delay, and filling time may be shortened by too long an AV delay. The AV delay at which the end of the A wave on transmitral flow coincides with complete closure of the mitral valve may be optimal. The subjects were 15 patients [70.3+/-12.3 (SD) years old] with an implanted DDD PM. Cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were measured by Swan-Ganz catheter. Transmitral flow was recorded by pulsed Doppler echocardiography. AV delay was prolonged stepwise by 25 msc. When the AV delay was set at 155+/-26 ms, the end of the A wave coincided with complete closure of the mitral valve. When the AV delay was prolonged 25, 50, 75, and 100 ms from this AV delay, the interval between the end of the A wave and complete closure of mitral the valve was prolonged 16+/-5, 39+/-6, 65+/-4 and 88+/-5 ms, respectively (r = 0.97, P<0.0001) and diastolic mitral regurgitation was observed during this period. Thus, the optimal AV delay may be predicted as follows: the slightly prolonged AV delay minus the interval between the end of the A wave and complete closure of the mitral valve. When the AV delay was set at 215 ms, there was a significant positive correlation between the predicted optimal AV delay (166+/-23 ms) and the optimal AV delay (CO: 161+/-26 msec, r = 0.93, P<0.0001, PCWP: 161+/-28 msec, r = 0.95, P<0.0001). In conclusion, optimal AV delay can be predicted by this simple formula: slightly prolonged AV delay minus the interval between end of A wave and complete closure of mitral valve at the AV delay setting.     

Growing cavernous haemangioma of the liver: 11-fold increase in volume in a decade

A 57 year old Japanese male was incidentally found to have a 7.5 cm diameter hepatic haemangioma. Eleven years later he was operated on because the haemangioma had grown into a 17 cm mass causing upper abdominal fullness. Volumetry on computerized tomograms disclosed that the haemangioma had grown from 123 cm3 to 1343 cm3 in volume. Quantitative documentation on growing hepatic haemangioma has been rare.     

Unfolding of tertiary structures of proteins

The unfolding pathway of lysozyme was investigated by carrying out the computer simulation. Taking into account the simultaneous change of both the dihedral angles ø and of a residue, we explore the detailed features of the conformational energy profiles. The triangle distance map shows that the lysozyme molecule is divided into three domains, 1–40, 41–101 and 102–129 in amino acid residue numbers (referred to as the domains I, II and III, respectively). The calculated unfolding process indicates that in the early stage of unfolding domain III located at the C-terminal begins to be detached from the other two, and then domain I can be unfolded. The long-range interactions between domains I and III stabilize the whole molecule and give the cooperative nature of the folding. The calculated unfolding pathway of lysozyme is consistent with the folding pathway proposed by Anderson & Wetlaufer [J. Biol. Chem. (1976). 251 , 3147–3153] who identified the disulfide bondings in the early stage of the glutathione regeneration. A simplified treatment of unfolding for myoglobin is also discussed in the Appendix.     

Ovarian mixed germ cell tumor composed of dysgerminoma, endodermal sinus tumor, choriocarcinoma and mature teratoma in a 44-year-old woman: Case report and literature review

A case of ovarian mixed germ cell tumor In a 44-year-old woman was examined. The tumor was well circumscribed, measured 15 times 11 times 10cm and appeared solid and partly cystic on the cut surface. Light microscopic examinations revealed that the tumor was composed of four different neoplastic germ cell elements, Intermingled with each other. They are: (i) choriocarcinoma, immunohistochemically positive for human placental lactogen (hPL) and human chorionic gonadotropin (hCG); (ii) dysgerminoma, positive for placental alkaline phosphatase; (iii) endodermal sinus tumor positive for α-fetoproteln (AFP); and (lv) mature teratoma. Among these histological types, dysgermlnoma occupied more than 50% of the neoplasm. The patient was diagnosed as a stage la ovarian mixed germ cell tumor and was subsequently treated with chemotherapy. A second-look laparotomy after completion of chemotherapy revealed no residual tumors in the abdomen and the patient Is alive and well 15 months after operation. This Is the fourth reported case of ovarian mixed germ cell tumor arising In patients over 40 years old.