Pharmacokinetics of a benzodithiin (RD3-0028) following aerosol treatment in rat

1. RD3-0028, a benzodithiin compound, has potent antiviral activity against respiratory syncytial virus (RSV) in cell culture. The compound also inhibits growth of RSV and improves pathologic changes of interstitial pneumonia in the immunosuppressed mouse when delivered by small-particle aerosol. 2. In the present study, the absorption, distribution and excretion of 14C-RD3-0028 were compared in rat following either a single aerosol treatment or oral administration. 3. The plasma concentration was maintained at the same level from 5 min to 1 h, and decreased with a half-life of 2.2 +/- 0.1 h for 1-8 h. 4. The excretion of radioactivity in the urine and faeces at 24 h after aerosol treatment was 89.3 and 4.5%, respectively, indicating that almost all the radioactivity was rapidly excreted in the urine. The excretion of total radioactivity was 98.9% within 168 h. 5. The concentrations of radioactivity in the lung and trachea following aerosol treatment were higher than those in other tissues, and were detected even at 72 h. 6. These results suggest that the aerosol treatment might be useful for delivering RD3-0028 to the respiratory tract of RSV-infected patients.     

Sentinel lymph node biopsy without axillary dissection after an intraoperative negative histological investigation in 358 invasive breast cancer cases

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an important treatment option for breast cancer patients, as it can accurately predict axillary status. Our previous study using dye with or without radioisotope showed the accuracy and sensitivity of SLNB to be 97% and 94%, respectively. Based on these results, axillary lymph node dissection (ALND) was eliminated starting in January, 1999 in patients with intraoperatively negative SLNB at our institution. The present study shows the results and outcomes of SLNB as a sole procedure for patients with invasive breast cancer. PATIENTS AND METHODS: Three-hundred-fifty-four patients and 358 cases of invasive breast cancer (4 bilateral breast carcinoma) treated with SLNB alone after an intraoperative negative SLNB were studied prospectively from January 1999 to December 2001. RESULTS: The number of the identified SLNs per case ranged from 1 to 8 (mean, 2.5). Of a total of 358 cases, 297 (83%) were treated with hormone therapy and/or chemotherapy, and 281 (78%) were treated with radiotherapy to the conserved breast (50 Gy+/-10 Gy boost), the axilla (50 Gy), or the both sites. After a median follow-up of 21 (range 6-42) months, no patient developed an axillary relapse. Four cases initially recurred in distant organs and one case in the conserved breast. CONCLUSIONS: Our results indicate that an intraoperative negative SLNB without further ALND may be a safe procedure when strict SLNB is performed. To better assess the safety, however, may require longer follow-up.     

Sodium overload through voltage-dependent Na(+) channels induces necrosis and apoptosis of rat superior cervical ganglion cells in vitro

Using the failure to exclude trypan blue as a criterion for cell death, we found that veratridine, the voltage-dependent Na(+) channel activator, exerted its toxicity to cultured sympathetic neurons in a dose-dependent manner (half-maximal toxicity occurred at 2 microM). The co-presence of tetrodotoxin completely reversed the toxicity only at concentrations of veratridine < 20 microM. Veratridine neurotoxicity was due to the influx of Na(+); a medium low in Na(+) (36 mM) completely abolished its neurotoxicity, whereas a Ca(2+)-free medium did not attenuate its neurotoxicity. Furthermore, the buffering action of 1, 2-Bis-(2-aminophenoxy)ethane-N,N,N',N',-tetraacetate (BAPTA) on veratridine-induced increase in intracellular Ca(2+) levels neither blocked veratridine neurotoxicity in normal medium, nor attenuated the low Na(+) effect. Elevated K(+) effectively blocked veratridine neurotoxicity in a Ca(2+)-dependent manner. Cytoplasmic pH measurements using a fluorescent pH indicator demonstrated that cellular acidification (from pH 7.0 to pH 6.5) occurred upon treatment with veratridine. Both veratridine-induced acidification and cell death were ameliorated by 5-(N-ethyl-N-isopropyl)amiloride, the specific inhibitor of the Na(+)/H(+) exchanger (IC(50) = 0.5 microM). Finally, necrosis occurred predominantly in veratridine neurotoxicity, but both staining with bis-benzimide and TUNEL analysis showed nuclear features of apoptosis in sympathetic neurons undergoing cell death.     

Recurrent exercise-induced acute renal failure in renal hypouricemia

We describe a male patient with four episodes of acute renal failure after strenuous exercise occurring between the age of 14 and 25 years. He was found to have low serum uric acid (0.4mgdl⁻¹ after recovery) and high fractional excretion of uric acid. A benzbromarone, pyrazinamide test suggested that renal hypouricemia was due to defective proximal tubular reabsorption of uric acid at a pre-secretory site. A renal biopsy revealed acute tubular necrosis, a renal computer tomography scan showed patchy contrast enhancement and a treadmill exercise test induced an immediate fall in creatinine clearance. These findings suggest that the cause of acute renal failure was renal vasoconstriction rather than obstruction by uric acid crystals.     

Whole-genome analysis of human astrocytic tumors by comparative genomic hybridization

Frozen sections of 35 astrocytic tumors of various histologic malignancies were analyzed by comparative genomic hybridization in an attempt to characterize the profile of genetic aberrations. Over 94% of the samples revealed DNA copy number aberrations, which increased with higher histological malignancy grades, and also involvement of more than one chromosome was seen in 85% of instances. The aberrations observed were mainly deletions and most frequently incorporated chromosomes 1p, 10, 19q, and 22q. On the other hand, gains or amplifications were detected only in glioblastomas. Additionally, such gains or amplifications were present in all tumor samples where the initial histopathological diagnosis was glioblastoma and immunohistochemical study disclosed p53 tumor suppressor protein negative and epidermal growth factor receptor positive immunoreactivity; such glioblastomas possessing p53 tumor suppressor protein positive and epidermal growth factor receptor negative immunoreactivity seldom displayed any gain. Thus, glioblastomas exhibiting two different profiles of genetic aberrations were recognized—one with and the other without any gains/amplifications. We speculate that the former variety is de novo glioblastoma.     

Comparative study on in vitro lymphocytotoxicity and mitogenicity of different antilymphocyte globulin (ALG) preparations

The lymphocytotoxicity and mitogenicity between six different ALG preparations on the clinical use world wide were compared. No significant difference in the lympholytic activity was observed between preparations and 100% cell lysis was achieved at a concentration of 50 micrograms/ml in the presence of complement. On the other hand, four preparations now in use in European countries and USA showed variable mitogenic activities on lymphocytes in the absence of complement, whereas two ALGs used in Japan did not. As the stimulatory effects of ALG on lymphocytes may contribute to the clinical outcome in the treatment of severe aplastic anemia (Kawano et al, 1988), these date can explain the poor clinical results of ALG therapy with those two preparations in Japan. Careful measures should be paid in the construction of treatment protocol and selection of ALG preparations to yield the best results.     

Effects of allergen controlled cosmetics on hyperpigmented dermatitis

Prior to the late 1970s, cosmetic dermatitis was quite common in Japan. Once sensitizers were established, in cosmetics, soaps, shampoos, and other commonly used substances, effective treatment was only possible if the cycle of recrudescence could be broken. The Allergen Controlled System accomplished this by preventing contact with the main contact sensitizers.Although the number of cases of pigmented cosmetic dermatitis has declined because of restrictions on the use of several major sensitizers, the Allergen Controlled System remains an effective treatment for the cases that still occur.     

Bacteriological study of cefminox in the field of obstetrics and gynecology

Cefminox (CMNX, MT-141), a new cephem antibiotic, was determined of its antibacterial activity against 304 clinical isolates with following results. CMNX was inferior to CEZ or CMZ in the activity against 78 isolates of Staphylococcus sp., but it was superior to these antibiotics in the activity against 104 isolates of E. coli. Against 53 isolates of Bacteroides sp., CMNX showed higher activity than CEZ or CMZ. In the activity against 69 isolates of Peptococcus sp. and Peptostreptococcus sp., CMNX was almost equal to CEZ.