The Effects of N-Benzoyl-β-alanine,a New Nephroprotective Drug,on the Distribution and Renal Excretion of Enprofylline in Rats

Abstract— The effects of the new nephroprotective drug N-benzoyl-β-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2·5 mg kg^?1 under three different steady-state plasma BA concentrations (100,200 and 400 μg mL^?1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 μg mL^?1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 μg mL^?1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

Interaction of Local Anaesthetics with Histamine H1 Receptors in Guinea-pig Ileum

The interaction of amine local anaesthetics and related compounds with histamine H₁ receptors was investigated in guinea-pig ileal longitudinal muscle. Quinacrine, chloroquine, tetracaine and procaine inhibited [³H]mepyramine binding to solubilized membrane from ileal muscle with pK_i values of 5.27 ± 0.11, 5.66 ± 0.01, 4.28 ± 0.08 and 3.97 ± 0.11, respectively. The pK_B values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 549 ± 0.11, 6.14 ± 0.09, 4.86 ± 0.06 and 4.58 ± 0·06, respectively, in reasonable agreement with the pK_i values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H₁ receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization. The results suggested that most of these local anaesthetics interacted competitively at histamine H₁ receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allo-sterically and inhibited desensitization through a separate action.     

Use of the Ultrasonic Microprobe to Evaluate Gastric Varices –Comparison with Endoscopic Color Doppler Ultrasonography–

Abstract: This study was designed to evaluate the usefulness of the ultrasonic microprobe (UMP), as compared with endoscopic color Doppler ultrasonography (ECDUS), in detecting gastric varices in 18 patients. The gastric varices detected were categorized as follows: 14 F₂ type varices, four F₃ type. Among the 18 cases, four had cardiac varices, nine cardiofornical varices, and five fundic varices. UMP was easily performed visually by using an endoscope with a UM-3R (20MHz) probe, inserted via the biopsy channel, and a display unit (Olympus EU-M20). ECDUS was performed using a PENTAX FG-32UA and a FG-36UX, 7.5MHz, convex type. The display monitor was a HITACHI EUB 565. We were able to clearly delineate the vessel images of gastric varices in all 18 patients using UMP. Although the overall features of the peri-gastric collateral veins could not be discerned with UMP, the color flow images of gastric varices and peri-gastric collateral veins were clearly visualized in all 18 patients using ECDUS. It was thus possible to determine blood flow direction using ECDUS. We found the use of UMP to be advantageous in terms of the ease of operation and the excellent view provided of gastric varices. The fact that, due to limited penetration, UMP inadequately delineates the peri-gastric collateral veins was determined to be a major drawback. Therefore, we recommend ECDUS for evaluating overall hemodynamics. It was, however, technically difficult to scan the fundal region because of the characteristics of the ECDUS instrument. Thus, we conclude that detailed evaluation of gastric varix hemodynamics is most successfully accomplished by using UMP in conjunction with ECDUS.     

SYSTEMIC LUPUS ERYTHEMATOSUS: A CASE-CONTROL EPIDEMIOLOGIC STUDY IN JAPAN

Background. Systemic lupus erythematosus (SLE) is designated by the Japanese government as one of the intractable diseases and all patients, who suffer from these diseases, are registered to get financial aid for treatment. Using newly registered SLE patients, a case-control study was conducted to evaluate potential risk factors. Methods. Two-hundred and eighty-two women SLE patients, newly registered to receive financial aid for treatment, and 292 randomly selected health examination participants at public health centers (controls) were surveyed from April 1988 through March 1990. By means of a self-administered questionnaire, data concerning demographic variables, smoking and drinking habits, past medical and reproductive history, and family history were collected. Results. Based on unconditional logistic regression analysis, the risk of SLE was significantly increased for current smokers (age-adjusted odds ratio (OR) = 2.31, 95% confidence interval (CI) (1.34–3.97). Alcohol and milk intake were inversely associated with risk. Family histories of asthma and collagen diseases, including SLE, were associated with significantly elevated risk of SLE (OR = 2.07, 95% ci 1.14–3.77; OR = 5.20, 95% CI 1.08–24.95, respectively). Regarding reproductive function, women with menarche at age 15 or later had significantly higher risk than those, who started menstruating before age 12 (OR = 3.82, 95% CI 1.66–8.81 for menarche at > 15 years and OR = 2.90, 95% a 1.14–7.39 for menarche at 16y). Conclusions. Our study suggests several risk factors, including smoking, family history, and reproductive history that may increase the risk of SLE.     

Pharmacokinetic Characteristics of 5-Fluorouracil and Mitomycin C in Intraperitoneal Chemotherapy

Abstract— Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5-fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi-permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5-Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5-fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half-life in the peritoneal fluid (t½_p) and the rate constant from the peritoneal fluid to the systemic circulation (k_a) were nearly equal for both 5-fluorouracil and mitomycin C (t½_p, 1·0 h for 5-fluorouracil and 1·3 h for mitomycin C; k_a 0·71 h^?1 for 5-fluorouracil and 0·68 h^?1 for mitomycin C), although the apparent volume of distribution (Vd_s/F) and clearance in the peritoneal cavity (CL_p) for mitomycin C (78 Lm^?2 and 1.8 L h^?1 m^?2) were about twice the values for 5-fluorouracil (149 L m^?2 and 0·8 L h^?1 m^?2).     

Different Antiphospholipid Antibody Specificities are Found in Association with Early Repeated Pregnancy Loss Versus Recurrent IVF-Failure Patients

PROBLEM: Patients having in vitro fertilization and embryo transfer (IVF-ET) failures show an increased incidence of antiphospholipid (aPL) antibodies; but controversy exists whether aPL can induce IVF-failure. This study was designed to compare aPL specificities between recurrent IVF-failure patients versus repeated early pregnancy loss (RPL) patients. METHOD OF STUDY: Anticardiolipin (aCL), lupus anticoagulant (LA), antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE), and antinuclear antibodies (ANA) were measured in 74 recurrent IVF-ET failure patients and compared with 273 early RPL patients ( < 10 weeks). RESULTS: An increased incidence of IgG-aPE and ANA was observed for both groups in comparison with controls. Patients with recurrent IVF-ET failure showed a significantly higher prevalence of IgG-aPS (P = 0.02) and IgG-aCL (P = 0.02) when compared with early RPL patients or controls. CONCLUSIONS: IgG-aPS and IgG-aCL may be responsible for some IVF-failures. Additional studies are needed to clarify the pathogenic role of IgG-aPS and IgG-aCL on IVF-ET failure.     

Squamous cell carcinoma in the renal pelvis of a horseshoe kidney

We report a rare case of squamous cell carcinoma in the renal pelvis of a horseshoe kidney. An 80-year-old woman was referred to the National Nagano Hospital for the examination of occult blood in her urine. Microscopic hematuria was found, but pyuria was not seen. Computed tomography and magnetic resonance imaging showed a mass in the left renal pelvis of the horseshoe kidney. No renal stone or hydronephrosis was found. Cytopathological examination in the voided urine specimen was positive. Left nephroureterectomy with the splitting of the isthmus of the horseshoe kidney was performed without renal pedicle clamping using a microwave tissue coagulator. No bleeding was encountered after separating the isthmus. A final pathological diagnosis of squamous cell carcinoma with a tumor thrombus was made. Lymph node metastasis had developed and rapidly progressed and the patient died of disseminated malignancy 4 months after the operation. We reviewed 24 cases of renal pelvic tumor in horseshoe kidneys previously reported in Japan. Seven cases (30%) included components of squamous cell carcinoma. The incidence is higher than that of renal pelvic tumors in the general population.     

Ultrastructure of quick-frozen and freeze-substituted chick osteoclasts

For comparison with chemically fixed osteoclasts, we prepared chick osteoclasts by quick freezing followed by freeze-substitution. In spite of technical difficulties this demonstrated that osteoclasts can be satisfactorily frozen in situ by the metal contact method. Ultrastructural differences were revealed between conventional fixation and quick freezing. Compared with conventional fixation, the quick freezing method appeared to improve preservation: (1) a discrete trilaminar plasma membrane and other intracellular membranes showed a smooth profile without undulation or rupture; (2) cytoskeletal components appeared to be clearer, straighter, and more numerous; (3) the interior of the ruffled finger contained interconnected lattice structures whereas highly organised microfilaments were seen in the clear zone; (4) well developed tubulovesicular structures (TVSs) that branched or anastomosed with each other were revealed in the cytoplasm; (5) the contents of intracellular membrane systems including the nuclear envelope, endoplasmic reticulum, and Golgi complex were stained to a various extent; (6) vesicles and vacuoles were much smaller, round and well-defined with electron-dense contents; (7) crystalline structures were seen at the extracellular channels of the ruffled border, in the lumen of TVSs, and in vesicles; (8) in some instances mitochondrial granules were visible; (9) within the resorptive lacuna, osteoclasts adhered to the degraded bone matrix without any intervening empty space.     

Prominent induction of cyclin B1 in G2/M renal cancer cells with butyrolactone 1

BACKGROUND: Butyrolactone 1 (BL) is a cyclin dependent kinase (CDK) inhibitor derived from Aspergillus terreus. None of the present drugs are effective for the treatment of renal cell carcinoma. The use of BL is expected to promote a new type therapy of renal cancer. METHODS: We investigated three human renal cancer cell lines: ACHN, OS-RC-2 and RCC10RGB, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and two-color flow cytometry. Simultaneous measurements of DNA content and cyclin expression allowed us to perform cell cycle specific analysis. Western blot analysis was performed using ACHN to represent cell lines. RESULTS: BL inhibited cell proliferation and caused cell accumulation at G2/M phase associated with the emergence of the third peak. Moreover, BL induced cyclin B1 over-expression in G2/M cells. These changes were quite definite, whereas cyclins D1, E and A showed no changes at all. Cyclin B1 accumulation was confirmed by western blot analysis. The chronological observation revealed that the emergence of the third peak preceded the regression of the increased cyclin B1 positive G2/M cells. These results suggested that BL accelerated cyclin B1 accumulation in G2/M cells, which then shifted to G1 phase without cell division. New G1 cells started DNA synthesis most likely as endoreduplication to form the third peak and the mechanism of cyclin B1 accumulation converted into down-regulation. CONCLUSION: BL induced significant cell kinetic interference in the tested human renal carcinoma cell lines. This might indicate the possibility of a new medical treatment modality for renal cancer.     

Hepatic angiomyolipoma pre-operatively diagnosed by imaging

An asymptomatic patient with pre-operatively diagnosed solitary angiomyolipoma is reported. The tumour was a well defined, fat density mass on computerized tomography (CT) and magnetic resonance imaging (MRI), and a hyperechoic nodule with a sharp margin on ultrasonography (US). The lesion was hypervascular on arteriography and CT during hepatic angiography. Chemical shift MRI confirmed the fat component within the lesion. Although a review of the literature shows this tumour to be rare and difficult to differentiate from a malignant lesion pre-operatively, the pre-operative diagnosis of angiomyolipoma is considered feasible when the characteristic findings as described here are present.