Activation of protein kinase C and nicotinamide adenine dinucleotide phosphate oxidase in leukocytes of spontaneously hypertensive rats.

The involvement of oxidative stress in polymorphonuclear leukocytes (PMN) in the pathogenesis of hypertension remains to be elucidated. We analyzed the generation of reactive oxygen species (ROS) by the circulating and peritoneally infiltrating PMN from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flow cytometric analysis revealed that ROS generation by PMN from SHR was higher than that from WKY before (at 6 weeks of age) and after (at 16 weeks of age) the onset of hypertension. In vivo, ROS generation by PMN from SHR, but not that by PMN from WKY, was significantly suppressed by 10-week treatment with 50 mg/kg/day carvedilol, and this treatment did not affect blood pressure. Western blotting analysis revealed that protein kinase C alpha (PKCalpha), but not PKCbetaI or betaII, was activated more strongly in PMN from SHR than in PMN from WKY. Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY. These results suggest that ROS generation by PMN is principally enhanced in SHR through activation of PKCalpha and p47phox.     

Bioavailability of mefenamic acid: influence of food and water intake

The influence of food and water intake on mefenamic acid (N-2,3-xylylanthranilic acid) bioavailability from commercial capsules of high bioavailability was studied in four healthy male volunteers. The drug was administered as a single oral dose of 250 mg, under fasting or nonfasting conditions, and a 4 X 4 Latin-square design was used. Eight blood samples were collected over a 24-h period following drug administration, and the drug plasma concentrations were determined by HPLC. The bioavailability of mefenamic acid from capsules was markedly influenced in the fasting subjects by the water but not by the food intake. A good correlation was found between the bioavailability and amount of water ingested with the drug in the fasting subjects. The area under the plasma concentration-time curve (AUC0-infinity) of mefenamic acid was highest when the capsule was taken with 50 mL of water or immediately after a meal. Increasing the amount of water from 50 to 500 mL in the fasting subjects caused a significant reduction in AUC0-infinity.     

Clinical evaluation of norfloxacin in gonococcal urethritis

Norfloxacin, a new quinolinecarboxylic acid derivative, was administered to 30 male patients with gonococcal urethritis at a daily dose of 600 mg for 7-21 days. The clinical response was evaluated after administration of 7 days as excellent; Negative culture of N. gonorrhoeae. WBC less than 3/hpf in first voided urine sediment, good; Negative culture, WBC greater than or equal to 3/hpf, and poor; Positive culture. The result was excellent in 14 cases and good in 16 cases. No subjective side effects were observed. The minimum inhibitory concentration (MIC) distribution against the clinically isolated 30 strains of N. gonorrhoeae ranged from 0.0096 micrograms/ml to 0.34 micrograms/ml. Seven of thirty strains were resistant to ABPC. The MIC of these 7 strains ranged from 0.018 micrograms/ml to 0.18 micrograms/ml. Seven cases with ABPC resistant strains had a similar clinical response to other cases. Twelve patients (40%) developed post gonococcal urethritis for 7-14 days after treatment. Clinical observation of this series suggests that a 7 day therapy of Norfloxacin for the patients with gonococcal urethritis is sufficiently effective and that treatment should be changed to other antibacterial agents in the case of post gonococcal urethritis, since continuous administration for more than 7 days of Norfloxacin is not so effective.     

Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette-Guérin immunotherapy

AIM: In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. METHODS: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12. RESULTS: After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. CONCLUSIONS: We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.     

Significance of lateral biopsy specimens during transrectal ultrasound-guided prostate biopsies in Japanese men

OBJECTIVES: Lateral biopsies are thought to have a better cancer detection rate compared with standard sextant biopsies. This study aimed to determine whether lateral peripheral zone biopsies in Japanese men who underwent transrectal ultrasound-guided prostate biopsies provided a significantly higher cancer detection rate than sextant biopsies. METHODS: Between 1999 and 2004, data were collected from 461 men who underwent prostate biopsy and had enough data regarding the performance of lateral biopsies for statistical analysis. There were two categories in this study: (i) patients who underwent sextant prostate biopsies; and (ii) patients who underwent sextant biopsies plus lateral biopsies. RESULTS: Prostate cancer was detected in 141 (30.6%) of 461 patients. It was detected in 24 (22.2%) of 108 patients who underwent sextant biopsies and 117 (33.1%) of 353 patients who underwent sextant plus lateral biopsies. Lateral biopsies were not associated with a statistically higher rate of positive biopsy findings; however, we found a significantly higher ratio of patients with positive findings in those with prostate specific antigen (PSA) levels 10 ng/mL (one of 71, 1.4%) among those who had positive cores only in lateral biopsy samples (P < 0.0001). CONCLUSIONS: Lateral biopsies did not show a significantly higher detection ratio of prostate cancer compared to sextant biopsies. However, lateral biopsies were more effective than sextant biopsies in patients with lower PSA levels. Our findings might be useful for the establishment of biopsy strategies to detect prostate cancer, especially in patients with lower PSA levels.     

Methamphetamine-induced behavioral alterations following repeated administration of methamphetamine

Repeated administration of a large dose of methamphetamine (MA) (25 mg/kg, i.p. twice daily for 4 days) to mice enhanced locomotor activity and decreased stereotyped behavior following a subsequent injection of MA. Simultaneous determinations of catecholamines revealed a depletion of brain dopamine. The moderate doses of haloperidol significantly enhanced MA-induced locomotor activity in mice. A significant enhancement of MA-induced locomotor activity was observed in the rats pretreated with 6-hydroxydopamine into the striatum, and this effect correlated negatively with the striatal dopamine level. These results suggest that hypofunction of striatal dopaminergic neuron systems induced by repeated administration of MA may be one of possible mechanisms of the enhancement of MA-induced locomotor activity due to the decrease of stereotyped behavior.     

Clinical studies on morphological changes in the prostate in patients with benign prostatic hypertrophy after antiandrogen therapy--by means of transrectal ultrasonotomography]

Transrectal ultrasonotomography is useful in following patients with benign prostatic hypertrophy, because prostatic shape and weight are precisely assumed. We studied the effect of chlormadinone acetate (CMA) on benign prostatic hypertrophy. CMA (50 mg/day) was administered to 30 patients with benign prostatic hypertrophy. Weight reduction over 10% of the gland was noticed in 24 cases (80%). Mictional conditions were improved in 70% subjectively and in 71.4% objectively. However, the number of nocturia decreased in only 18.9%. Reduction rate of the weight was unrelated with the weight of prostate before administration of CMA. Duration of administration of CMA and the reduction rate were estimated. There was no definite difference in reduction rate for the first 15 months, but there was a slightly high reduction rate after administration of CMA for more than 24 months. In 3 cases, the shape and weight of prostate were studied after discontinuation of CMA. The size of prostate showed a tendency to increase gradually.     

Synthesis of 4,5-diarylthiazole derivatives as blood platelet aggregation inhibitors

A number of 2-substituted 4,5-diphenylthiazoles were synthesized by the nucleophilic substitution of 2-methylsulfonyl-4,5-diphenylthiazole with various sodium alkoxides, amines, and carbanions of active methylene compounds. 2-Methylsulfonyl-4,5-diphenylthiazole was obtained by the potassium permanganate oxidation of 2-methylthio-4,5-diphenylthiazole in the presence of a phase-transfer catalyst. 2-Ethoxy-4,5-bis(4-methoxyphenyl) thiazole was prepared in a similar manner. 2-Ethynyl-4,5-diphenylthiazoles were synthesized by the palladium catalyst cross-coupling reaction of 2-iodo-4,5-diphenylthiazole with monosubstituted acetylenes. These compounds were tested for inhibitory activity against blood platelet aggregation in vitro. Among them, 2-alkoxy-, and 2-(4-methylpiperazin-1-yl)-4,5-diphenylthiazole were found to have potent inhibitory activity.