Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325.

BACKGROUND AND PURPOSE: Vasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325. EXPERIMENTAL APPROACH: We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models. KEY RESULTS: Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats). CONCLUSION: TASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.

Comparison of the collecting efficiency of microbiological air samplers.

It is important to evaluate the prevention of nosocomial infections caused by airborne micro-organisms in healthcare facilities. For that purpose, the use of an air sampler is required. A comparison of the collecting efficiency of air samplers has not been studied so far using a single culture medium. Use of the same culture medium is necessary because of the variation of the cultivation efficiency with different culture media. In this study a statistically significant difference in collecting efficiency among air samplers was observed in case of SCDA (soybean casein digest agar) culture medium, but not SCDALP (soybean casein digest agar lecithin polysorbate) culture medium. In addition, a statistically significant difference of the cultivation efficiency was observed between SCDA and SCDALP culture media (P<0.05). These results suggest that any air sampler can be used with SCDALP culture medium.

[Significance of interferon alpha therapy for advanced renal cell carcinoma. Fukushima Renal Cancer Study Group].

We ranked prognostic factors to retrospectively evaluate the clinical significance of interferon alpha (IFN-alpha) therapy in patients with Robson stage IVB renal cell carcinoma. A total of 44 Robson stage IVB renal cancer patients were divided into 2 groups, one with more than 6 months administration of IFN-alpha (3-7 times a week: group A) and another without any IFN-alpha administration. The distribution of these 2 groups was not randomized. In addition to IFN-alpha therapy, survival was analyzed with respect to performance status (PS), mass reductive nephrectomy, concomitant use of other cytotoxic therapies, the number of metastatic organs, growth type, site of metastasis and the period of diagnosis, using a multivariate method with Cox proportional hazards regression. The multivariate analysis showed administration of IFN-alpha to be the most significant factor influencing a good prognosis. Improved survival was also significantly correlated with slow growing type and good PS. Among group A, a significant favorable prognosis was obtained in patients with the responses of no change (NC), partial response (PR) and complete remission (CR) 6 months after initiating administration of IFN-alpha, as well as with good PS and a slow growing type carcinoma. We conclude that IFN-alpha therapy might improve the prognosis of patients with Robson stage IVB renal cell carcinoma, especially, in cases when a greater than NC response is obtained after 6 months administration of IFN-alpha.

[Histological effects of short term endocrine therapy on prostatic cancer].

BACKGROUND: The objective of this study is to investigate the pathological changes which occurred in prostatic cancer shortly after the commencement of endocrine therapy. METHODS: Fourty-three patients underwent radical prostatectomy immediately after the short term endocrine therapy (treatment period was within one month) and the histological pictures of operative specimens were compared to those obtained from the pretreatment biopsy specimens. RESULTS: Degenerative changes of cancer cells, such as nuclear and cytoplasmic vacuole, collapse of the cytoplasm and the appearance of naked hyperchromatic nucleus were noticed after the short term endocrine therapy. Especially in the cases which were histologically evaluated to be poorly differentiated in the biopsy specimens, not only degenerative changes but also destruction of cancer nests caused by cell death were observed. The histological effects affected by short term endocrine treatment had no relation to the prognosis, but in the cases of stage D2, the pathological grade judged by post-therapeutic specimens were found to be useful for the prediction of prognosis. CONCLUSION: Endocrine therapy induces remarkable pathological changes in prostatic cancer within a very short time after beginning treatment.

[Flow cytometric analysis of prostatic adenocarcinomas after hormone therapy].

A DNA ploidy pattern of prostatic adenocarcinoma was studied by flow cytometry using the formalin-fixed, paraffin-embedded tissues obtained from 65 patients. These patients received hormone therapy preoperatively. Forty cases (61.5%) showed a diploid pattern, and 25 (38.5%) an aneuploid pattern. Comparing this ploidy pattern with histological classification, the aneuploid pattern was found in 13 cases (52%) of poorly differentiated group, 12 cases (48.0%) of moderately differentiated group and 0 case (0%) of well differentiated group. Thus, rate of aneuploid pattern increased with an increase in the grade of malignancy. Five years survival rate was 62.6% in the diploid group while it decreased to 30.9% in the aneuploid group. There was a significant difference between the two groups. In 23 cases with stage D, the ploidy pattern of primary region could be compared with that of metastatic region (lymph nodes). The prognosis of patients who exhibited the aneuploid pattern in metastatic region was significantly worse than that of other patients. These data suggested that flow cytometric DNA analysis of prostatic cancer materials after hormone therapy also produces meaningful information in predicting the prognosis of prostatic cancer.

[S-phase cells of human bladder tumors by in vivo bromodeoxyuridine labeling].

At the time of operation, 10 patients with bladder tumors were given an intravenous infusion of bromodeoxyuridine (BrdU, 250 mg) to label the cells in the DNA synthesis phase (S-phase). The removed tumor specimens were stained immunohistologically using anti-BrdU monoclonal antibody. The percentage of BrdU-labeled cells (S-phase cells) were calculated for each specimen, and expressed as Labeling Index (LI). The average LI of G1, G2 and G3 tumors were 0.9%, 2.3% and 11.9%, respectively. LI was almost parallel to pathological grade. In cases of G2 tumor, LI was varied from 0.2 to 6.2%. The higher LI, the more invasive was the tumor. The patient with the highest LI (12.2%) showed lung metastasis postoperatively and died 6 months after operation. S-phase cells were scattered along the basal layer in G1 papillary tumors, and were observed also near the superficial layer in G2 tumors. In cases of non-papillary tumors, S-phase cells were observed irregularly in various layers. This method will give us useful information on evaluation for malignancy and cell kinetics of bladder tumor.

Glycyrrhetinic acid derivatives: anti-nociceptive activity of deoxoglycyrrhetol dihemiphthalate and the related compounds.

The possible inhibitory effect of deoxoglycyrrhetol dihemiphthalate (I) and the related compounds (18 beta-olean-9(11),12-diene-3 beta,30-diol) (II) and (olean-11,13(18)-diene-3 beta, 30-diol) III derived from glycyrrhetinic acid has been examined on acetic acid-induced writhing in mice. The compounds inhibited writhing dose-dependently. Their ED50 values were 14, 31 and 22 mg kg-1 for I, II, and III, respectively. The compounds like aspirin, also significantly suppressed PGE2 production in peritoneal fluid together with the writhing response. The results suggests that the analgesic effect of deoxyglycyrrhetol dihemiphthalate and the related compounds is partially due to inhibition of PGE2 production.

Clinical application of extracorporeal shock wave lithotripsy using microexplosions.

Extracorporeal stone disintegration using a chemical explosive (10 mg. lead azide) as an energy source of underwater shock waves was performed in 105 patients 11 to 72 years old who had stones in the upper urinary tract. We used a prototype disintegrator in this series. The over-all rate free of stones 3 months after treatment was 82 per cent. Shock wave therapy was performed alone in 77 patients (73 per cent), while the remainder required combined treatment with percutaneous and/or transurethral lithotripsy. The most common complications were colic pain (30 per cent) and fever (23 per cent). In 4 patients other complications, that is bacteremia, gastrointestinal bleeding, ureteral injury and subcapsular renal hematoma, were observed but they were treated conservatively with no serious adverse effects. Our study demonstrates the safe use of this method for clinical treatment.

Partial and complete adenine phosphoribosyltransferase deficiency associated with 2,8-dihydroxyadenine urolithiasis: kinetic and immunochemical properties of APRT.

We have studied adenine phosphoribosyltransferase (APRT) in the hemolysates from the families of 2,8-dihydroxyadenine urolithiasis associated with partial deficiency of APRT (the Japanese type) and complete deficiency of APRT (the null type). The APRT in the control subjects was found to be heat-stable at the physiological concentration of phosphoribosylpyrophosphate (PRPP), which was close to the value of its Km for PRPP. The APRT in the Japanese type showed 10 times higher Km values for PRPP and needed a comparably increased level of PRPP for stability in vitro. No change in red cell PRPP was found in the Japanese type of APRT deficiency. The content of APRT enzyme protein was decreased in the hemolysates of the Japanese type, probably due to its lability at the level of PRPP present in the cells. The heterozygote of the null type also had labile enzyme molecules at the physiological PRPP concentration.

Extracorporeal stone disintegration using chemical explosive pellets as an energy source of underwater shock waves.

Extracorporeal renal stone disintegration using a chemical explosive pellet (lead azide 10 mg.) as an energy source of underwater shock waves has been successfully performed in animals. The shock wave was observed by holographic interferometry. Shock wave generation was performed by a reflector whose configuration was part of a pseudoellipsoid. The explosions were conducted 10 to 100 times for each animal and the stone (extracted human renal calculus or model calculus of activated alumina) placed in the renal pelvis was disintegrated satisfactorily. Negative findings in explorative laparotomy and histological examination, except for minor bleeding in several tubular lumina of the kidney, indicated that the method was clinically applicable.

Computed tomography and composition of renal calculi.

The attenuation values of computed tomography were studied in 50 recovered renal calculi of more than 10 mm in diameter, in the hope of determining the composition of calculi in situ. The attenuation value of various calculi (mean +/- s.d.) in a 5 mm slice with a maximal rectangular region of interest was as follows (Hounsfield units); mixed calcium oxalate and phosphate 1,555 +/- 193 (n = 22), magnesium ammonium phosphate 1,285 +/- 284 (n = 18), calcium oxalate 1,690 (n = 1), calcium phosphate 1,400 (n = 2), cystine 757 +/- 114 (n = 5) and uric acid 480 (n = 2). Attenuation values ranging from 500 to 1,600 overlapped for various calculi, except those composed of uric acid calculi. There was no correlation between the attenuation value and the mineral content such as calcium or magnesium per unit weight of calculus. The mineral content per unit volume seemed to be attributable to the attenuation value. From the present results we conclude that the determination of calculous composition by the attenuation value is possible only for oxalate calculi of more than 1,600 and uric acid calculi of less than 500 attenuation value, provided that the proper CT slice location, the region of interest and the appropriate calculus size can be determined.