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.     

Expression of cathepsin D and epidermal growth factor receptor in stage III cervical carcinomas

Cathepsin D and epidermal growth factor receptor (EGFR) antigens are related to tumor invasion, metastasis, progression, and recurrence. To assess the prognostic significance of the expression of these two antigens, biopsy specimens consecutively obtained from 216 patients with stage III cervical carcinomas (191 with squamous cell carcinomas and 25 with adenocarcinomas), who were treated with radiotherapy, were investigated immunohistochemically. The positive rate of cathepsin D expression in squamous cell carcinomas was 74%, significantly higher than the 47% observed in adenocarcinomas ( P  = 0.015). The EGFR positive rate in squamous cell carcinomas was 33%, somewhat higher than the 16% in adenocarcinomas ( P  = 0.088). The chi-square test and Kaplan–Meier method showed no significant relationship between the expression of either cathepsin D or EGFR and the prognosis in these patients. These results indicate that in stage III cervical carcinomas cathepsin D and EGFR expression do not correlate with prognosis.     

Cystic lymphangioma of the gall-bladder: A case report

Intra-abdominal cystic lymphangiomas are rare lesions that can be difficult to diagnose. We present a report of a patient with a giant multilocular cystic lesion in the abdomen. Ultrasonography and computed tomography scans of the abdomen revealed that the cyst had originated in the gallbladder fossa. There was some calcification and thickening of the cyst wall. Endoscopic retrograde cholangiopancreatography demonstrated a medially deviated common bile duct, an elongated cystic duct and an inferior compressed gallbladder. There was no apparent communication between the cyst and the biliary tract; however, an abdominal angiogram revealed that the lesion was supplied by a branch of the cystic artery. Histological findings obtained intra-operatively were consistent with a cystic lymphangioma. Its characteristic histology was observed in the subserous layer of the gall-bladder. This case is a rare instance of a cystic lymphangioma originating in the gall-bladder.     

Assessment and treatment of liver disease in Japanese haemophilia patients

Summary. We studied the prevalence of the hepatitis C virus (HCV), human immunodeficiency virus (HIV) and GB virus C or hepatitis G virus (GBV-C/HGV), and characteristics of infections in Japanese haemophilia patients. Haemophilia patients were highly infected with HCV (88.2%) because of frequent use of unheated blood concentrates. Analysis for HCV genotypes revealed characteristics of HCV infection in haemophilia patients. Japanese haemophilia patients were highly infected with rare genotypes in Japan: genotype 1a (26.5%), genotype 3 (14.5%) and genotype 4 (2.4%). HIV infection was observed in 32.3% of haemophilia patients. HCV quasispecies (clones) and direct sequencing were investigated in patients with a single HCV genotype in the hypervariable region 1 of HCV, which resulted in a high degree of diversity. This indicates that even a single genotype of HCV might have multiple origins. GBV-C/HGV infection was noted in 20.9% of Japanese haemophilia patients. Over 40 haemophilia patients with chronic hepatitis C have been treated with interferon alpha for 6 months at total doses of 480–720 million units. About 38% showed clearance of HCV RNA from serum. Six patients with HIV infection were included in the study and they did not show eradication of HCV from the serum. This might derive from that they had high serum HCV RNA titers and genotype 1a or 1b. Histologic assessment was performed in 36 haemophilia patients with HCV. No case showed a histologically normal liver. Hepatic fibrosis in the biopsy specimens was classified into five stages of fibrosis and compared with serum hepatic fibrosis markers. Serum hyaluronic acid mostly correlated with hepatic fibrosis (γ= 0.78, P < 0.0001) followed by type IV collagen (γ= 0.38, P < 0.05). This suggests that estimation of serum fibrosis markers might be substituted for liver biopsy in haemophilia patients.     

Serum hyaluronic acid reflects the effect of interferon treatment on hepatic fibrosis in patients with chronic hepatitis C

Changes in serum hyaluronic acid (HA) in 35 patients treated with interferon (IFN) were studied and the histological change in fibrosis was analysed. Serum HA levels and hepatitis C virus (HCV) RNA were followed from the start of therapy to 12 months after completion of treatment. Histological changes in pre- and post-treatment liver biopsies were assessed using a modified Knodell's scoring system. The serum levels of HA (r = 0.79; P<0.0001) correlated with the degree of fibrosis more closely than with that of amino terminal peptides of type III procollagen (PIIIP; r = 0.45; P<0.05) or type IV collagen (IV-C; r = 0.42; P<0.05). Only complete responders (CR) had a significant decrease in serum levels of HA and IV-C (P<0.05), in parallel with histological improvement (P<0.01). Neither partial responders (PR) nor non-responders (NR) had significant changes in histological scores and in serum levels of fibrotic markers. Significant differences were observed between CR and NR, both in HA levels (P<0.01) and PIIIP levels (P<0.05) 12 months after the cessation of treatment. These results suggest that serum HA is an indicator of the extent of fibrosis in chronic hepatitis C. Serial determinations of serum HA levels may be of use for monitoring the histological response of hepatic fibrosis to IFN treatment in chronic hepatitis C.     

Serum gonadotrophin and sex steroid hormone levels during mid-follicular and mid-luteal phases in hyperprolactinaemic women with regular menstrual cycles

Summary. Hyperprolactinaemia was found in 15 of 135 infertile patients with regular menstrual cycles, biphasic basal body temperature record and no galactorrhoea. In those 15 women, mean serum prolactin levels during the mid-follicular and mid-luteal phases of the menstrual cycle were 29.8 (SEM 1.8) ng/ml and 29–5 (SEM 1.3) ng/ml, respectively. Although serum FSH and LH levels were similar in normal and hyperprolactinaemic women, serum oestradiol level during the mid-follicular phase was subnormal in hyperprolactinaemic women ( P <0.05). In contrast, serum oestradiol and progesterone levels during the mid-luteal phase and luteal phase length were similar in nor-moprolactinaemic and hyperprolactinaemic groups. The results suggest that Hyperprolactinaemia is associated with defects of follicle development as measured by oestradiol production during the mid-follicular phase, but not with corpus luteum function as measured by progesterone production during the mid-luteal phase, and luteal phase length.     

Feedback mechanism in sulpiride-induced hyperprolactinaemia

Summary. Feedback of oestrogen on gonadotrophin release was studied in five normally cycling normoprolactinaemic women who were rendered moderately hyperprolactinaemic by oral administration of sulpiride (150mg daily) for 11 consecutive days. Five patients with peptic ulcer, who had been given 150 mg of sulpiride for 3–18 months and had chronic marked hyperprolactinaemia were also studied. Ethinyl oestradiol (200μg) was administered by mouth daily for 4 consecutive days and serum concentration of prolactin, luteinizing hormone (LH), follicle- stimulating hormone (FSH) and oestradiol were measured by a doubleantibody radioimmunoassay for 11 days. Oral administration of ethinyl oestradiol caused an initial decrease followed by a rebound of LH with a peak in all the women tested. The serum FSH levels showed only the initial decrease, followed by a slight rebound. Serum oestradiol levels decreased during oral administration of ethinyl oestradiol in all the women. The results of the present investigation suggest that oestrogen feedback effect on LH release is maintained in sulpiride-induced hyperprolactinaemic women as well as in women with normal cycles.