Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test (OECD): Familiarization Using Cyclophosphamide

Combined Repeat Dose and Reproductive/Developmental ToxicityScreening Test (OECD): Familiarization Using Cyclophosphamide.TANAKA, S., KAWASHIMA, K., NAITO, K., USAMI, M., NAKADATE, M.,IMAIDA, K., TAKAHASHI, M., HAYASHI, Y., KUROKAWA, Y., AND TOBE,M. (1992A, Y., AND TOBE, M. (1992). Fundam. Appl. Toxicol. 18,89–95. A familiarization study was conducted on the "Combined RepeatDose and Reproductive/Developmental Toxicity Screening Test(ReproTox)" proposed by the OECD. Cyclophosphamide (CP) at dosesof 6.7, 4.5, 3, 2, and 0 mg/kg body wt was given daily by gavageto groups of 12 male and 12 female Sprague-Dawley rats. As aresult, anemia and leukopenia were evident in treated males.The absolute and relative thymus and spleen weights were decreasedin treated rats. Histopathologically, atrophy of the thymus,spleen, and bone marrow was observed. With respect to the reproductive/developmentaltoxicity, dose-dependent increases in postimplantation lossof fetuses and postnatal death were found in dams given CP.The body weight of pups treated with CP was significantly loweredin a dose-related manner. Thus the results demonstrated mostof the known toxicological properties of CP, except the adverseeffects on spermatogenesis and fertility. Therefore ReproToxcan be considered as a useful screening test for assessing repeatdose and reproductive/developmental toxicity of existing chemicalsof high production volume.     

Clinical study of complicated urinary tract infection using ''The UTI Criteria (Draft Fourth Edition)'': Measurement methods for pyuria

OBJECTIVE: To evaluate the influences the change of the measurement method of pyuria from conventional centrifuged sediment to microchamber uncentrifuged urine for the results of evaluation of antimicrobial agents in clinical study against complicated urinary tract infections. From the viewpoint of international harmonization of judgement criteria, the recent method for counting white blood cells (WBC) in urine has changed from using uncentrifuged urine to using a microchamber in all countries. METHODS: Targeted diseases were non-catheterized complicated urinary tract infection, and cefcapene pivoxil hydrochloride or levofloxacin were used as antimicrobial drug. Pyuria was examined using the counting chamber method, a quantitative method using uncentrifuged urine with a microchamber, and the sedimentation method. RESULTS: Overall clinical efficacy in early evaluation by the two methods in measuring pyuria was evaluated as different in eight patients (7.3%). It was rated excellent in 63 (52.9%), moderate in 32 patients (26.9%) and poor in 24 (20.2%) with an efficacy rate of 79.8% using the counting chamber method, and excellent in 68 (57.1%), moderate in 27 (22.7%) and poor in 24 (20.2%) with an efficacy rate of 79.8% using the conventional sedimentation method CONCLUSION: No significant difference was seen between the two methods of WBC count in urine.     

DNA analysis at p53 locus in carcinomas arising from pleomorphic adenomas of salivary glands: Comparison of molecular study and p53 immunostaining

Where and how frequently p53 abnormalities are involved in the development of pleomorphic adenoma (PA) and its malignant progression to carcinoma was investigated. The presence of p53 gene abnormalities was analyzed in eight patients with carcinoma in pleomorphic adenoma (CPA) by polymerase chain reaction (PCR)-based assays and immunohistochemistry. Normal salivary gland tissue, adenomatous, transitional and carcinomatous areas were microdissected from archival microslides and analyzed for allelic deletions of the p53 gene using two microsatellite markers at the p53 locus; dinucleotide (CA)_n repeat and pentanucleotide (AAAAT)_n repeat. Loss of heterozygosity (LOH) of the p53 gene was detected in 5796 of adenomas, 86% of transitional lesions and 86% of carcinomas. In contrast, overexpression of p53 oncoprotein was noted immunohistochemically in 13% of adenomas, 50% of transitional areas and 75% of carcinomas. All of the tumors with immunoreactivity for p53 oncoprotein demonstrated LOH. Moreover, when LOH was present in adenomatous or transitional areas, the identical LOH was always detected in the corresponding carcinomatous areas in the same CPA tumors. These findings indicate that p53 gene mutation is an early event and occurs frequently at an early stage of precancerous lesions and may be responsible for most cases of malignant transformation of PA.     

DNA analysis at p53 locus in adenoid cystic carcinoma: Comparison of molecular study and p53 immunostaining

Abnormalities of the p53 tumor suppressor gene were investigated in 22 foci from 14 adenoid cystic carcinomas (ACC) by polymerase chain reaction (PCR)-based assays for dinucleotide (CA)_n and pentanucleotide (AAAAT)_n repeat polymorphisms and by immunohistochemical staining for oncoprotein expression. Adenoid cystic carcinomas were divided into lower grade (tubular and cribriform) subtypes and higher grade (trabecular and solid) subtypes. Histologically identified tumor cells were precisely microdissected from archival microslides and were used for molecular analysis. The overall frequency of p53 gene mutations detected by PCR-loss-of-heterozygosity (LOH) analysis was 57% and was higher than the frequency of overexpression of p53 oncoprotein detected by immunostaining (43%). In the molecular analysis of individual histological subtype foci, the number of foci with p53 gene mutation was slgnificantly greater in the higher grade subtype foci than in the lower grade subtype foci and was greatest in solid-type foci (100%). In all six tumors in which histologically different foci were present In the Same tumors, mutations of the p53 gene were detected. When tumor heterogeneity of the p53 gene was present among different histological foci in the same tumors, the mutations were always detected in the higher grade foci. When lower and higher grade foci were present in the same tumors, the identical mutations detected In the lower grade foci were present in the corresponding higher grade foci. These findings indicate that abnormaliies of the p53 gene are involved in carcinogenesis and/or progression of this tumor and, furthermore, suggest that molecular analyses of ACC may provide information of prognostic importance.     

Clinical impact of tamsulosin on generic and symptom-specific quality of life for benign prostatic hyperplasia patients: Using international prostate symptom score and Rand Medical Outcomes Study 36-item Health Survey

AIM: To examine the efficiency of alpha1-blocker treatment on disease-specific and generic quality of life (QOL) in men with clinically diagnosed benign prostatic hyperplasia (BPH), the improvement of QOL scores with International prostate symptom score (I-PSS) and Rand Medical Outcomes Study 36-item Health Survey (SF-36) was prospectively analyzed. METHODS: A total of 68 newly diagnosed patients with symptomatic BPH that satisfied all inclusion and none of the exclusion criteria were prospectively recruited. All patients received 0.2 mg/day of tamsulosin for 12 weeks. All patients underwent pretreatment documentation of lower urinary tract symptoms (LUTS) and assessment of symptom-specific QOL. Symptoms and general health-related QOL (HRQOL) were assessed using the I-PSS and SF-36, respectively. Also, other objective variables, such as prostate volume, maximal urinary flow and postvoid residual urine volume, were evaluated. RESULTS: After 12 weeks, decrease in I-PSS was 27% compared with baseline (from 16.4 +/- 7.18 to 11.9 +/- 7.56). All questionnaires in the I-PSS showed improvement after tamsulosin treatment and the I-PSS QOL score was improved from 4.51 +/- 1.14 to 3.17 +/- 1.38 (P < 0.0001) at 12 weeks after tamsulosin administration. In intragroup comparisons of HRQOL scores with age-gender adjusted SF-36 Japanese national norms, three SF-36 subscales (bodily pain, BP; social function, SF; and mental health, MH) were worse in the BPH group aged over 70 years, while younger BPH groups aged <70 had better mean SF-36 physical function (PF) scores compared with age-gender adjusted Japanese national norms. In the BPH group with a prostatic volume > or =20 mL, three mean SF-36 scales (BP, SF and MH) were significantly improved after tamsulosin treatment. It is noteworthy that these SF-36 subscales were identical to those observed to worsen in the older BPH group compared to Japanese national norms. CONCLUSIONS: Treatment with tamsulosin for symptomatic BPH patients is associated with significant improvement in the generic HRQOL, in addition to disease-specific QOL and symptoms, at 3 months after drug administration. In particularly, for generic HRQOL with SF-36, tamsulosin treatment can efficiently improve three mean SF-36 subscales (BP, SF and MH) that are decreased in older BPH patients.     

Serum α2-macroglobulin–trypsin complex and early recognition of severe acute pancreatitis after endoscopic retrograde pancreatography

Serum α₂-macroglobulin-trypsin complex (α₂M-T) was measured to differentiate the elevation of serum pancreatic enzymes caused by severe acute pancreatitis from simple elevation after endoscopic retrograde pancreatography (ERP). A patient with severe acute pancreatitis demonstrated marked elevation of serum α₂M-T. In patients without severe acute pancreatitis, serum αM-T did not rise in spite of elevated serum pancreatic enzymes. In conclusion, abdominal pain with elevated serum α₂M-T can be an early diagnostic clue to severe acute pancreatitis after ERP.     

Dissimilarity in the mechanisms of action of KRN2391, nicorandil and cromakalim in canine renal artery

Abstract— In the present study, we examined the mode of action of KRN2391 (N-cyano-N′-(2-nitroxyethyl)-3-pyridinecarboximida-mide monomethanesulphonate) in isolated canine renal artery compared with those of nicorandil and cromakalim. KRN2391 (10^?8-3 × 10^?5 m ), nicorandil (10^?7-3 × 10^?4 m ) and cromakalim (10^?8-3 × 10^?5 m ) relaxed renal arteries contracted by 25 Mm KCl in a concentration-dependent manner. KRN2391-induced relaxation was inhibited by methylene blue (10^?5 m ) and glibenclamide (10^?6 m ). Nicorandil-induced relaxation was inhibited by methylene blue, but not by glibenclamide. The concentration-relaxation curve for cromakalim displayed a rightward parallel shift in the presence of glibenclamide. In the control observation, KRN2391 and nicorandil also produced full relaxation, but cromakalim did not. The present results suggest that KRN2391 acts as both a nitrate and a potassium channel opener, and nicorandil acts only as a nitrate and only in canine renal artery.     

Effect of sildenafil on arterial stiffness, as assessed by pulse wave velocity, in patients with erectile dysfunction

BACKGROUND: The problems of patients with erectile dysfunction have been recognized, leading to the emergence of sildenafil, which has led to successful treatment in many cases. The purpose of this study is to examine the effect of sildenafil on the pulse wave velocity of patients with erectile dysfunction. METHODS: Fifteen patients with erectile dysfunction were enrolled for this study. The brachial/ankle pulse wave velocity was determined before dosing and at 30, 60, 120, and 180 min after dosing with 25 or 50 mg of sildenafil citrate. Concurrently, the changes in blood pressure, heart rate, and brachial/ankle pulse wave velocity were measured. For the consideration of revised brachial/ankle pulse wave velocity by blood pressure, the systolic blood pressure-derived brachial/ankle pulse wave was also investigated, and we classified and examined those results with and without risk factors for arteriosclerosis. RESULTS: The systolic blood pressure decreased significantly at 60 min after dosing compared with the placebo control. The heart rate decreased at 120 min after dosing compared with the placebo control but that decrease was not significant. The brachial/ankle pulse wave velocity transiently decreased at 30 or 60 min after dosing compared with the placebo control, but the decrease was not significant; however, the systolic blood pressure-derived brachial/ankle pulse wave velocity decreased significantly. In those patients with risk factors for arteriosclerosis, the pulse wave velocity decreased significantly. CONCLUSION: In patients with erectile dysfunction who were administered sildenafil, the pulse wave velocity, along with blood pressure, tended to decrease transiently after dosing. There is a possibility that sildenafil affects the improvement of erectile dysfunction via the decrease of pulse wave velocity, especially in patients with risk factors for arteriosclerosis.     

Comparison of the effects of KRN2391 and other coronary dilators on porcine isolated coronary arteries of different sizes

Abstract— The present study was performed to determine whether KRN2391 (N-cyano-N′-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulphonate), a novel vasodilator, shows different effects on porcine isolated coronary arteries of different sizes. The vasodilating effects of KRN2391 on porcine large (2·5–3·0 mm outer diam.) and small (0·8–1·0 mm) coronary arteries were also compared with those of cromakalim, nicorandil, nifedipine, nitroglycerin and adenosine. The relaxant effects of these drugs were examined in coronary arteries contracted by 25 Mm KCl. Nitroglycerin caused greater relaxation in large vessels than in small vessels. In contrast, adenosine, nifedipine and cromakalim caused greater relaxation in small vessels. However, there was no difference between large and small vessels in the relaxing effects of KRN2391 and nicorandil. These unique features of KRN2391 and nicorandil appear to be beneficial in ischaemic heart disease.