Prognosis and clinical features of intractable epilepsy: A prospective study

Abstract  Of the epileptic patients who were treated for ≥ 5 years until the end of 1990 and had more than four seizures in 1990, 63 patients had been treated without interruption until the end of 1995. We analyzed their clinical courses from 1990 to 1995 prospectively. More than half the subjects were diagnosed with temporal lobe epilepsy. Twenty cases had presumed etiology, and 32 had neuropsychiatric complications. Of the subjects whose seizures were not controlled with conventional antiepileptic drugs (AED), 11 cases demonstrated significant improvement when new AED; that is, lamotrigine, vigabatrin, clobazam, topiramate, tiagabine or CGP33101 were added. However, 10 patients did not respond to new AED. Presumed etiology, neuropsychiatric complications, multiple epileptic foci in EEG and abnormalities on head CT or MRI were characteristics of the patients whose seizures were resistant to new AED.     

Biopharmaceutics: Topical Delivery of Keloid Therapeutic Drug,Tranilast, by Combined Use of Oleic Acid and Propylene Glycol as a Penetration Enhancer: Evaluation by Skin Microdialysis in Rats

Topical delivery of tranilast (N-(3,4-dimethoxycinnamoyl)anthranic acid), an inhibitor of collagen synthesis and a therapeutic drug for keloid and hypertrophic scar, was examined, in rats, with oleic acid alone or a combination of oleic acid and propylene glycol as penetration enhancer. Evaluation was by measurement of the concentration of tranilast in plasma and in the dialysate from skin microdialysis. When tranilast at a dose of 1.5 mg was applied topically as an ethanol solution containing 5% polyvinylpyrrolidone on a dorsal skin surface (2.25 cm²), the maximum concentration of tranilast in skin dialysate was approximately 2 μM. When 10 or 20% oleic acid was added to the same ethanol solution the maximum concentration of tranilast in the dialysate increased to 10–20 μM, and this value was further increased to 60 μM by the addition of a combination of oleic acid (10 or 20%) and propylene glycol (10%) to the solution. With the combination of oleic acid and propylene glycol the area under the plot of the concentration of tranilast in skin dialysate against time between 0 and 4 h (AUC_0–4) was more than 400-fold that after intravenous administration. The transdermal bioavailability of tranilast as assessed by the AUC_0–4 of tranilast in plasma, was 0.2% of the dose applied in the ethanol solution, 3–5% of that applied in the ethanol solution containing oleic acid, and 14–16% of that applied in the ethanol solution containing both oleic acid and propylene glycol. These results suggest that the topical delivery of tranilast with an absorption enhancer such as a mixture of oleic acid and propylene glycol might be a more effective medication than oral administration of tranilast for the treatment of keloid and hypertrophic scar.     

Effects of the anti-ICAM-1 monoclonal antibody on dextran sodium sulphate-induced colitis in rats

Increased expression of intercellular adhesion molecule-1 (ICAM-1) in the colon of inflammatory bowel disease (IBD) has been reported. We evaluated the effects of monoclonal antibodies to ICAM-1 on acute colitis induced by dextran sodium sulphate (DSS) in rats. Colitis was induced by feeding rats 3% DSS for 7 days. Anti-ICAM-1 antibody or vehicle alone was injected intraperitoneally in rats daily from day 0 to day 6. On day 7 the rats were killed and colitis was evaluated histologically. Prophylactic treatment with anti-ICAM-1 significantly attenuated colonic damage, neutrophil infiltration and the shortening of the colon in DSS colitis. Our findings demonstrate that ICAM-1 plays an important role in this model of inflammatory bowel disease. Although this study does not directly address the effect of anti-ICAM-1 therapy in IBD, our findings encourage experiments using therapies that target ICAM-1 in rats with already developed disease.     

Intranodal palisaded myofibroblastoma with so-called amianthoid fibers: A report of two cases with a review of the literature

Two cases of intranodal myofibroblastoma, a rare primary spindle cell tumor of the lymph node, are described. The tumors arose in the Inguinal or proximal region of the thigh of one middle-aged and one elderly Japanese male. The tumors were well-demarcated and composed of a fascicular proliferation of spindle cells with focal nuclear palisading and acellular stellate-shaped collagen-rich areas (so-called amianthoid fibers), and were associated with hemorrhagic areas. lmmunohistochemically, the tumor cells were positive for vimentin and muscle actin. Together with ultrastructural findings of intracytoplasmic microfilaments with focal denslties and profiles of welldeveloped, rough endoplasmic reticulum, these features reinforced the conclusion of myofibroblastic or smooth muscle differentiation of the tumor cells. One of the tumors was analyzed by flow cytometry and was shown to be DNA dlploid. The present report provides cllnicopathological findings of the first two Japanese cases of intranodal myofibroblastoma.     

Natural Products: Effects of Sho-saiko-to Extract on Fibrosis and Regeneration of the Liver in Rats

Sho-saiko-to, one of the most widely used Chinese herbal preparations, has long been used for the treatment of chronic liver diseases. We have investigated its effect in retarding the process of liver fibrosis and accelerating liver regeneration, especially its effect on Ito cells that are thought to be deeply involved with liver fibrosis. Sho-saiko-to extract and its active constituents were orally administered to rats with dimethy lnitrosamine-induced liver-injury. After treatment with sho-saiko-to extract hepatic function improved, histopathological results confirmed repair of liver tissue, and retinoid levels increased. On the other hand, when active constituents of sho-saiko-to extract were administered alone, liver retinoid levels remained low, implying that interaction among active constituents of the extract was suppressing Ito cell activation. When sho-saiko-to extract was administered to 70% hepatectomized normal and liver-injured rats, liver weight, the number of S-phase-cells and retinoid levels increased with time. However, these changes were different for normal and liver-injured rats, suggesting that the site of action of sho-saiko-to extract in regenerating liver is different for normal and liver-injured rats. These results show that sho-saiko-to extract was useful for suppressing the activation of Ito cells.     

Biodistribution of Cyclosporin Encapsulated in Liposomes Modified with Bioadhesive Polymer

The purpose of this investigation was to study the possibility of renewing the immunosuppressive activity of cyclosporin by formulating the compound in liposomes modified with bioadhesive polymers. The liposomes prepared were evaluated both pharmacokinetically and pharmacodynamically. Tissue distribution and plasma pharmacokinetics of cyclosporin and model dye, sudan black, which is as hydrophobic as cyclosporin, were studied in rats after intravenous infusion (10 mg kg^?). The immunosuppressive efficacy of liposomal cyclosporin preparations was studied in the allogenic rat-heart-transplantation model, where cyclosporin therapy (10 mg kg^?) continued for one week. The entrapment of sudan black in liposomes modified with bioadhesive polymers resulted in higher sudan black delivery to the spleen and the liver than with standard sudan-black-loaded liposomes. Among the modified liposomes, those modified with carbopol 941 showed the most remarkable enhancing effect on the delivery of sudan black to these organs and total plasma clearance of sudan black decreased to 38.6 ± 7.8 mL h^? kg^? (standard liposomes, 58.9 ± 64 mL h^? kg^?). Delivery of cyclosporin to the spleen and the liver was increased approximately twofold by modifying the liposomes with carbopol 941. In the preliminary study on the allogenic rat-heart-transplantation model, the mean survival days of the graft were 18.8 ± 2.9 days for the group receiving cyclosporin liposomes modified with carbopol 941, 14.2 ± 4.4 days for the group receiving standard cyclosporin liposomes and 7.6 ± 0.5 days for the group receiving cyclosporin solution. The encapsulation of cyclosporin in liposomes modified with bioadhesive polymer enhanced the residence time of cyclosporin in the systemic circulation, resulting in approximately twofold greater delivery of cyclosporin to the spleen and liver. However, in the allogenic rat-heart-transplantation model no significant difference was detected between the immunosuppressive efficacy of cyclosporin encapsulated in bioadhesive polymer-modified liposomes and that encapsulated in standard liposomes.     

Hepatic Clearance of ONO-5046, a Novel Neutrophil Elastase Inhibitor,in Rats and in the Rat Perfused Liver

The hepatic clearance of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)phenylsulphonyl-amino]benzoyl]aminoacetic acid), a low-molecular-weight neutrophil elastase inhibitor, has been investigated in rats and in the rat perfused liver. This ester was easily hydrolysed to its inactive metabolite EI-601 (N-[2-[(4-hydroxy-phenyl)sulphonylamino]benzoyl]aminoacetic acid) in liver homogenate and in erythrocytes suspension in-vitro. On the other hand, it was stable in biological media such as plasma and whole blood, which contain plasma proteins. Scatchard plot analysis of ONO-5046 binding to bovine serum albumin (BSA) in-vitro indicated that the association constant (K) and number of binding sites (n) were 6.91 times 10⁴ (M^?1) and 4.33, respectively. Thus, ONO-5046 (100 μM) would bind to plasma proteins to an extent >99% at physiological plasma-protein concentrations. The total plasma clearance of ONO-5046 in rats was constant (approximately 9 mL min^?1 kg^?1) under different steady-state plasma concentrations (5–50 μM) a value equivalent to the hepatic clearance. In the rat perfused liver, the hepatic extraction ratio of ONO-5046 was significantly reduced by adding BSA to the dosing solution. Thus, the relatively low hepatic clearance of ONO-5046, which has an ester linkage in its structure and is naturally susceptible to enzymatic hydrolysis, was found to be because of the extremely high protein-binding of the compound.     

Lack of association between the incidence of testicular germ cell tumors and Y-chromosome haplogroups in the Japanese population

BACKGROUND: Despite being relatively uncommon, testicular germ cell tumors (TGCT) are the most common malignant disease in young men. Epidemiological studies concerning patients with testicular cancer indicate that the most of them have poor semen quality or testicular dysgenesis. However, many studies have shown that the Y chromosome harbors many candidate genes responsible for spermatogenesis process and development and maintenance of the germ cells. The Y chromosome is thought to have a relationship with the formation and progression of TGCT. MATERIALS AND METHODS: To verify this relationship, we investigated if there is any correlation between the Y chromosome structural variations presented as different haplogroups and the occurrence of TGCT in the Japanese population. Using combined haplogroups based on typing of three Y chromosome polymorphic binary markers, we analyzed 68 TGCT derived from Japanese patients together with randomly selected 104 unrelated healthy Japanese matched male controls who were confirmed as residents of the same geographic area. RESULTS: Our findings showed a lack of association between the incidence of TGCT and the different Y- chromosome haplogroups in Japanese population. CONCLUSION: We concluded that there are no significant variations in males from different Y chromosome lineages regarding their susceptibility or resistance for developing TGCT. The previously hypothesized role of the Y chromosome in the development of TGCT is still uncertain and needs further verification.     

Transperineal extended biopsy improves the clinically significant prostate cancer detection rate: A comparative study of 6 and 12 biopsy cores

BACKGROUND: We evaluated the improvement in the rate of prostate cancer detection when using a 12-core transperineal biopsy protocol including transitional zone biopsy. METHODS: Between April 2003 and November 2004, 247 consecutive men underwent transperineal systemic 12-core biopsy of the prostate. Six cores were obtained at the peripheral zone, four at the transitional zone and two at the apex. We examined the cancer detection rate in each of the 12 cores, and also determined the improvement of cancer detection resulting from the extensive 12-core versus standard 6-core biopsy. RESULTS: Using the extensive 12-core biopsy, prostate cancer was detected in 98 cases (39.7%). Prostate-specific antigen (PSA), PSA density, the positive rate in digital rectal examination and transrectal ultrasound findings were significantly higher in the prostate cancer group than in the non-prostate cancer group, and prostate volume was larger in non-prostate cancer group. Every site showed almost the same positive rate, between 17.8 and 21.5%. There were 20 cases which were positive in the extended biopsy, but negative in the sextant. The detection improved significantly (20.4%). The improvement of cancer detection in extended biopsy was better in men with PSA levels of 10 ng/mL or less (28.9%), PSA density 0.3 or less (25.8%), negative digital rectal examination (23.3%), and negative transrectal ultrasound (21.6%). Of these twenty patients, no cases with insignificant tumor were detected in the six prostatectomy cases. In particular, three cases of the six were transitional-zone-only cancer. CONCLUSION: Transperineal extended 12-core biopsy including 4 transitional zone cores is a more useful procedure than transperineal 6-core biopsy. Routine transitional zone biopsy, that is different from transrectal biopsy, might be useful for detecting biologically significant cancer.