Intestinal Absorption of Stable Cyclic Dipeptides by the Oligopeptide Transporter in Rat

Intestinal absorption of four cyclic dipeptides was studied in the everted small intestine of the rat. Cyclic seryltyrosine (cyclo(Ser-Tyr)) was stable enough to be transported whereas linear seryltyrosine was not. The absorption clearance of cyclo(Ser-Tyr) was concentration-dependent, and for cyclo(Ser-Tyr) at 125 μM decreased in the presence of glycylsarcosine (10 mM) or cephalexin (10 mM), which were reported to be absorbed by oligopeptide transporter. The absorption clearance was also reduced at 4°C and in the presence of 1 mM dinitrophenol. Kinetic analysis of cyclo(Ser-Tyr) absorption showed that K_m and V_max were 19.8 μM and 0.295 nmol min^?1 cm^?1, respectively. It was also suggested that cyclic aspartylphenylalanine and cyclic histidylphenylalanine were absorbed by oligopeptide transporters, but cyclic histidylproline was not. The absorption clearance of cyclo(Ser-Tyr) in the control was much higher than the value of the correlation line representing a plot of passive transport (which was obtained from the absorption clearance of cyclic peptides in the presence of glycylsarcosine (10 mM)) against hydrophobicity (oil-water partition coefficient). These results indicate that cyclo(Ser-Tyr) is absorbed by the oligopeptide transporter.     

Drug Metabolism: Activation of 11 β-Hydroxysteroid Dehydrogenase by Dehydroepiandrosterone Sulphate as an Anti-hypertensive Agent in Spontaneously Hypertensive Rats

The anti-hypertensive properties of dehydroepiandrosterone sulphate (DHEAS) have been investigated by studying its effects on blood pressure, on serum concentrations of corticosterone and dehydrocorticosterone, and on 11 β-hydroxysteroid dehydrogenase (11 β-HSD) activity in spontaneously hypertensive rats (SHR). SHR were given intraperitoneal injections of DHEAS (10 mg day^?1 for 70 days) from six to 16 weeks of age. The blood pressure–time curve was significantly (P<0.05) suppressed immediately after administration of DHEAS. There was no difference between the heart rates of control and DHEAS groups. Serum concentrations of corticosterone and dehydrocorticosterone in the DHEAS group were significantly (P < 0.05) lower than those of the control group. The dehydrocorticosterone/corticosterone concentration ratio was, however, significantly (P < 0.05) higher in the DHEAS group, suggesting that treatment with DHEAS enhanced the overall interconversion of corticosterone to dehydrocorticosterone. The activity of 11 β-HSD in specific organs of the DHEAS group was affected, characteristic changes being increases in the kidney (14–58%), decreases in the liver (11–27%) and no change in the testis. Direct addition of DHEAS to 11 β-HSD preparations from the kidneys of control SHR had the same effect as that observed in the in-vivo experiments. The fall in serum corticosterone in the DHEAS group is considered to be related, at least partly, to increased activity of kidney 11 β-HSD. The inverse correlation of kidney 11 β-HSD activity with serum corticosterone and blood pressure (—r = 0.628, P < 0.01, and —r = 0.478, P < 0.05, respectively) suggest that DHEAS delayed the development of hypertension in SHR by selective promotion of kidney 11 β-HSD activity which in turn resulted in lower serum concentrations of corticosterone and its minimal aldosterone-like activity.     

Estimation of myocardial damage in Kawasaki disease using antimyosin antibody

In a retrospective study, 121 children with Kawasaki disease (KD) were investigated to determine (i) the incidence of myocardial damage using the antimyosin antibody (AMA) titer; (ii) the differences in the electrocardiograms between the AMA-positive and -negative patients; and (iii) the effect of treatment with intravenous gamma globulin (IVGG) on the AMA. Comparisons were made with 117 normal children (controls). Patients with KD showed a significantly higher mean AMA titer and more patients were positive for AMA than the controls. The AMA titer in the KD group was not related to the presence of coronary artery lesions. Electrocardiograms obtained during the acute and the convalescent stage of KD revealed that patients positive for AMA had a significantly lower voltage of T wave in lead V6 at week four than at week two of illness, whereas patients negative for AMA showed no T wave change after week two. The group treated with IVGG showed a significantly lower AMA titer than that not given IVGG. These observations suggest that myocardial damage occurs in some patients with KD which is unrelated to the presence of coronary artery lesions and that the treatment with IVGG reduces the AMA titer in patients with KD.     

Familial occurrence of congenital bile duct cysts

Congenital bile duct cysts are now a well-documented anomaly of the biliary tree, and have become more common in Japan. Familial occurrence of congenital bile duct cysts, however, is extremely rare, with only six reported cases in the literature. We report a familial pattern of congenital bile duct cysts in a mother and her daughter. A 33-year-old female was admitted for evaluation of right upper quadrant abdominal pain and fever 6 days after an uneventful delivery of her second child. A com- puted tomography (CT) and ultrasound scan (US) revealed an obstructed biliary tract. Percutaneous transhepatic biliary drainage was then performed, and a cholangiogram revealed a Scholtz type B choledochocele without an anomalous connection of the pancreaticobiliary ducts. Endoscopic US demonstrated that the choledochocele was associated with a stone in the cyst. A pylorus-preserving pancreatoduodenal resection was performed, and a histological study revealed that the choledochocele was lined by biliary mucosa without evidence of malignancy. The newborn infant had an abdominal tumour. An US and CT revealed a congenital bile duct cyst. An operation was performed and the intraoperative cholangiogram showed an Alonso-Lej type I congenital bile duct cyst with an anomalous connection of the pancreaticobiliary ducts. Whether congenital bile duct cysts are hereditary remains to be elucidated.     

Prostate gland volume is a strong predictor of biopsy results in men 70 years or older with prostate-specific antigen levels of 2.0–10.0 ng/mL

PURPOSE: The incidence of prostate cancer, benign prostatic enlargement and serum level of prostate-specific antigen (PSA) increase with patient age. Intermediate elevation of PSA in elderly populations is apt to be considered insignificant. We evaluated the impact of PSA and prostate volume on the presence of non-palpable prostate cancer in elderly men with an intermediate level of PSA. MATERIALS AND METHODS: Clinical records of 154 men 70 years or older, with non-cancerous digital rectal examination findings and with serum PSA levels of 2.0-10.0 ng/mL, who underwent initial 6- to 10-core transrectal prostate biopsy, were reviewed for prostate volume, number of biopsy cores, PSA and associated parameters. Stepwise logistic regression and receiver operating characteristic (ROC) models were used to determine the impacts of the parameters on the biopsy results. RESULTS: Overall cancer detection rate was 40/154 or 26.0%. Prostate-specific antigen showed no significant association with the presence of prostate cancer (P = 0.59, Mann-Whitney U-test), while prostate volume did (P < 0.0001). On stepwise logistic regression analysis, prostate volume (P = 0.024, 95% CI 1.008-1.116) and biopsy core density (P = 0.017, 95% CI 4.76-7.12 x 10(6)) were independently associated with a cancer diagnosis, whereas PSA density was not an independent factor for a positive biopsy result. The area under the ROC curve for prostate volume was significantly superior to that of PSA (0.802 vs. 0.529; P = 0.012). CONCLUSIONS: In men 70 years or older with gray zone PSA, prostate cancer patients are equally distributed over any PSA range. Although PSA has less impact on cancer presence than mere prostate volume, prostate cancer would be detected in a substantial proportion of older patients with PSA levels of 2.0-10.0 ng/mL.     

Pharmacological and Pharmacokinetic Characteristics of YM435, a Novel Dopamine DA1-Receptor Agonist,in Anaesthetized Dogs

Time-course of plasma concentration of unchanged drug of the dopamine DA₁-receptor agonist (–)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrate (YM435), and its effects on blood pressure and renal blood flow were investigated in anaesthetized dogs. Continuous intravenous infusion of YM435 (0.1–3 μg kg^? min^?) rapidly increased renal blood flow and lowered blood pressure in a dose-dependent manner. These effects remained generally stable throughout the infusion period. Following the start of infusion, plasma concentration of unchanged drug also rose rapidly and dose-dependently and remained virtually constant throughout the infusion period. A significant correlation was observed between log YM435 plasma concentration and the increase in renal blood flow (r = 0.93, P < 0.0001) and between the former and the reduction in blood pressure (r = 0.93, p < 0.0001). The present results indicate that YM435 produces renal vasodilatation and lowering of blood pressure in a dose-dependent manner and with rapid onset following continuous intravenous infusion, and that these effects are generally stable throughout the period of infusion. These haemodynamic effects of YM435 were in good agreement with the time-course of plasma concentration of unchanged drug.     

Long-term sequential changes of antibody to p40tax in HTLV-I carrier mothers and children

Antibody to p40^tax (anti-p40^tax) in serum specimens obtained sequentially from a human T cell lymphotropic virus type I carrier population of mothers and children were assayed. The prevalences of anti-p40^tax at the initial sampling were 88% (7/8) in children and 55% (16/29) in mothers. Two of the seven positive children lost their anti-p40^tax during the investigation period, resulting in a final prevalence of 63% (5/8) in children. However, anti-p40^tax status was constant in all the 22 mothers with multiple serum samples (15 remained positive and seven remained negative). A decline in the absorbance value of EIA for anti-p40^tax was observed in seven of the 15 anti-p40^tax positive mothers. This decline may result in the disappearance of anti-p40^tax in some of them.